The ubiquitin codes in cellular stress responses

Abstract

Ubiquitination/ubiquitylation, one of the most fundamental post-translational modifications, regulates almost every critical cellular process in eukaryotes. Emerging evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses, from exogenous factors to cellular reactions, causing a dazzling variety of functional consequences. Various forms of ubiquitin signals generated by ubiquitylation events in specific milieus, known as ubiquitin codes, constitute an intrinsic part of myriad cellular stress responses. These ubiquitination events, leading to proteolytic turnover of the substrates or just switch in functionality, initiate, regulate, or supervise multiple cellular stress-associated responses, supporting adaptation, homeostasis recovery, and survival of the stressed cells. In this review, we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses, while discussing how stresses modulate the ubiquitin system. This review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses and discusses some important questions that may warrant future investigation.

Key words： ubiquitin; E3 ligase; environmental stresses; intercellular stresses; stress response; homeostasis

References

1 Abdelmohsen K, Srikantan S, Yang X et al. Ubiquitin-mediated proteolysis of HuR by heat shock. EMBO J 2009;28:1271–82.

2 Ai H, Sun M, Liu A et al. H2B Lys34 Ubiquitination induces nucleosome distortion to stimulate Dot1L activity. Nat Chem Biol 2022;18:972–80.

3 Akimov V, Barrio-Hernandez I, Hansen SV et al. UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites. Nat Struct Mol Biol 2018;25:631–40.

4 Akman M, Belisario DC, Salaroglio IC et al. Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons. J Exp Clin Cancer Res 2021;40:1–17.

5 Akturk A, Wasilko DJ, Wu X et al. Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector. Nature 2018;557:729–33.

6 Albanese A, Daly LA, Mennerich D et al. The role of hypoxia-inducible factor post-translational modifications in regulating its localisation, stability, and activity. Int J Mol Sci 2020;22:268.

7 Aprile-Garcia F, Tomar P, Hummel B et al. Nascent-protein ubiquitination is required for heat shock–induced gene downregulation in human cells. Nat Struct Mol Biol 2019;26:137–46.

8 Aravind L, Koonin EV. The U box is a modified RING finger—a common domain in ubiquitination. Curr Biol 2000;10:R132–4.

9 Asaoka T, Almagro J, Ehrhardt C et al. Linear ubiquitination by LUBEL has a role in Drosophila heat stress response. EMBO Rep 2016;17:1624–40.

10 Avitan-Hersh E, Feng Y, Vaisman AO et al. Regulation of eIF2α by RNF4 promotes melanoma tumorigenesis and therapy resistance. J Investig Dermatol 2020;140:2466–77.

11 Balaji V, Hoppe T. Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly. F1000Res 2020;9:1–8.

12 Ballinger CA, Connell P, Wu Y et al. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 1999;19:4535–45.

13 Bankir L, Bouby N, Trinh-Trang-Tan M-M. The role of the kidney in the maintenance of water balance. Baillieres Clin Endocrinol Metab 1989;3:249–311.

14 Barford D. Structural interconversions of the anaphase-promoting complex/cyclosome (APC/C) regulate cell cycle transitions. Curr Opin Struct Biol 2020;61:86–97.

15 Barghouth PG, Thiruvalluvan M, LeGro M et al. DNA damage and tissue repair: what we can learn from planaria. Semin Cell Dev Biol 2019;87:145–59.

16 Barnes BM. Freeze avoidance in a mammal: body temperatures below 0°C in an arctic hibernator. Science 1989;244:1593–5.

17 Bartke T, Pohl C, Pyrowolakis G et al. Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol Cell 2004;14:801–11.

18 Bassermann F, Frescas D, Guardavaccaro D et al. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 2008;134:256–67.

19 Becker JR, Clifford G, Bonnet C et al. BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination. Nature 2021;596:433–7.

20 Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discovery 2022;21:181–200.

21 Bento CF, Fernandes R, Ramalho J et al. The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal. PLoS One 2010;5:e15062.

22 Bettaieb A, Averill-Bates DA. Thermotolerance induced at a mild temperature of 40 C alleviates heat shock-induced ER stress and apoptosis in HeLa cells. Biochim Biophys Acta, Mol Cell Res 2015;1853:52–62.

23 Bhogaraju S, Kalayil S, Liu Y et al. Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 2016;167:1636–1649.e13.

24 Bhogaraju S, Bonn F, Mukherjee R et al. Inhibition of bacterial ubiquitin ligases by SidJ–calmodulin catalysed glutamylation. Nature 2019;572:382–6.

25 Black MH, Osinski A, Gradowski M et al. Bacterial pseudokinase catalyzes protein polyglutamylation to inhibit the SidE-family ubiquitin ligases. Science 2019;364:787–92.

26 Bohgaki T, Bohgaki M, Cardoso R et al. Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome. PLoS Genet 2011;7:e1001381.

27 Bohgaki M, Bohgaki T, El Ghamrasni S et al. RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks. Proc Natl Acad Sci USA 2013;110:20982–7.

28 Bond U, Schlesinger MJ. Ubiquitin is a heat shock protein in chicken embryo fibroblasts. Mol Cell Biol 1985;5:949–56.

29 Bond U, Schlesinger MJ. The chicken ubiquitin gene contains a heat shock promoter and expresses an unstable mRNA in heat-shocked cells. Mol Cell Biol 1986;6:4602–10.

30 Bond MJ, Chu L, Nalawansha DA et al. Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Cent Sci 2020;6:1367–75.

31 Bondeson DP, Smith BE, Burslem GM et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol 2018;25:78–87.

32 Brocker C, Thompson DC, Vasiliou V. The role of hyperosmotic stress in inflammation and disease. Biomol Concepts 2012;3:345–64.

33 Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294:1337–40.

34 Burgos JI, Morell M, Mariángelo JIE et al. Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes. Apoptosis 2019;24:785–97.

35 Cairó M, Campderrós L, Gavaldà-Navarro A et al. Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis. EMBO Rep 2019;20:e46832.

36 Calzado MA, De La Vega L, Möller A et al. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol 2009;11:85–91.

37 Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 2014;21:396–413.

38 Cappadocia L, Lima CD. Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chem Rev 2018;118:889–918.

39 Carlson N, Rogers S, Rechsteiner M. Microinjection of ubiquitin: changes in protein degradation in HeLa cells subjected to heat-shock. J Cell Biol 1987;104:547–55.

40 Cassavaugh JM, Hale SA, Wellman TL et al. Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem 2011;112:3882–90.

41 Catrina S-B, Okamoto K, Pereira T et al. Hyperglycemia regulates hypoxia-inducible factor-1α protein stability and function. Diabetes 2004;53:3226–32.

42 Chen D, Li M, Luo J et al. Direct interactions between HIF-1α and Mdm2 modulate p53 function. J Biol Chem 2003;278:13595–8.

43 Chen P-C, Bhattacharyya BJ, Hanna J et al. Ubiquitin homeostasis is critical for synaptic development and function. J Neurosci 2011;31:17505–13.

44 Chen Z, Liu L, Cheng Q et al. Mitochondrial E3 ligase MARCH 5 regulates FUNDC 1 to fine-tune hypoxic mitophagy. EMBO Rep 2017;18:495–509.

45 Chen X, Li Z, Yong H et al. Trim21-mediated HIF-1α degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis. Cancer Lett 2021;508:115–26.

46 Chen Q, Zheng W, Guan J et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ 2023;30:137–51.

47 Cheng L, Zhang W, Hu J et al. Characterization of the key region and key phosphorylation sites of EcaICE1 for its molecular interaction with EcaHOS1 protein in Eucalyptus camaldulensis. Res Square 2020.

48 Clague MJ, Urbé S, Komander D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol 2019;20:338–52.

49 Clarke HJ, Chambers JE, Liniker E et al. Endoplasmic reticulum stress in malignancy. Cancer Cell 2014;25:563–73.

50 Clouaire T, Rocher V, Lashgari A et al. Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures. Mol Cell 2018;72:250–262.e6.

51 Connell P, Ballinger CA, Jiang J et al. The co-chaperone CHIP regulates protein triage decisions mediated by heatshock proteins. Nat Cell Biol 2001;3:93–6.

52 Crinelli R, Bianchi M, Radici L et al. Molecular dissection of the human ubiquitin C promoter reveals heat shock element architectures with activating and repressive functions. PLoS One 2015;10:e0136882.

53 Cullen KE, Sarge KD. Characterization of hypothermia-induced cellular stress response in mouse tissues. J Biol Chem 1997;272:1742–6.

54 Dai Q, Zhang C, Wu Y et al. CHIP activates HSF1 and confers protection against apoptosis and cellular stress. EMBO J 2003;22:5446–58.

55 Dai Y, Zhang J, Xiang J et al. Calcitriol inhibits ROS-NLRP3-IL-1β signaling axis via activation of Nrf2-antioxidant signaling in hyperosmotic stress stimulated human corneal epithelial cells. Redox Biol 2019;21:101093.

56 Daks A, Petukhov A, Fedorova O et al. The RNA-binding protein HuR is a novel target of Pirh2 E3 ubiquitin ligase. Cell Death Dis 2021;12:1–14.

57 Danno S, Nishiyama H, Higashitsuji H et al. Increased transcript level of RBM3, a member of the glycine-rich RNA-binding protein family, in human cells in response to cold stress. Biochem Biophys Res Commun 1997;236:804–7.

58 Daugaard M, Nitsch R, Razaghi B et al. Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes. Nat Commun 2013;4:2180.

59 de Jager M, Dronkert ML, Modesti M et al. DNA-binding and strand-annealing activities of human Mre11: implications for its roles in DNA double-strand break repair pathways. Nucleic Acids Res 2001;29:1317–25.

60 den Engelsman J, Keijsers V, de Jong WW et al. The small heat-shock protein αB-crystallin promotes FBX4-dependent ubiquitination. J Biol Chem 2003;278:4699–704.

61 Deng L, Meng T, Chen L et al. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther 2020;5:1–28.

62 Densham RM, Garvin AJ, Stone HR et al. Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat Struct Mol Biol 2016;23:647–55.

63 Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem 2009;78:399–434.

64 Dietz L, Ellison CJ, Riechmann C et al. Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. Science 2023;379:1112–7.

65 Dikic I, Wakatsuki S, Walters KJ. Ubiquitin-binding domains—from structures to functions. Nat Rev Mol Cell Biol 2009;10:659–71.

66 Dinkova-Kostova AT, Kostov RV, Canning P. Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Arch Biochem Biophys 2017;617:84–93.

67 Doil C, Mailand N, Bekker-Jensen S et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 2009;136:435–46.

68 Dong C-H, Agarwal M, Zhang Y et al. The negative regulator of plant cold responses, HOS1, is a RING E3 ligase that mediates the ubiquitination and degradation of ICE1. Proc Natl Acad Sci USA 2006;103:8281–6.

69 Dong K, Wei R, Jin T et al. HOIP modulates the stability of GPx4 by linear ubiquitination. Proc Natl Acad Sci USA 2022;119:e2214227119.

70 Dou H, Buetow L, Sibbet GJ et al. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat Struct Mol Biol 2013;20:982–6.

71 Dove KK, Klevit RE. RING-between-RING E3 ligases: emerging themes amid the variations. J Mol Biol 2017;429:3363–75.

72 Drané P, Brault M-E, Cui G et al. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 2017;543:211–6.

73 Duda DM, Olszewski JL, Schuermann JP et al. Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism. Structure 2013;21:1030–41.

74 Eddins MJ, Varadan R, Fushman D et al. Crystal structure and solution NMR studies of Lys48-linked tetraubiquitin at neutral pH. J Mol Biol 2007;367:204–11.

75 Ehrmann JF, Grabarczyk DB, Heinke M et al. Structural basis of how the BIRC6/SMAC complex regulates apoptosis and autophagy. bioRxiv 2022.

76 Elia AE, Wang DC, Willis NA et al. RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks. Mol Cell 2015;60:280–93.

77 Epstein AC, Gleadle JM, McNeill LA et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43–54.

78 Escribano-Díaz C, Orthwein A, Fradet-Turcotte A et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 2013;49:872–83.

79 Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 2005;434:605–11.

80 Fang NN, Chan GT, Zhu M et al. Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress. Nat Cell Biol 2014;16:1227–37.

81 Fang S, Cheng Y, Deng F et al. RNF34 ablation promotes cerebrovascular remodeling and hypertension by increasing NADPH-derived ROS generation. Neurobiol Dis 2021;156:105396.

82 Fell VL, Schild-Poulter C. The Ku heterodimer: function in DNA repair and beyond. Mutat Res/Rev Mutat Res 2015;763:15–29.

83 Feng L, Chen J. The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat Struct Mol Biol 2012;19:201–6.

84 Feng X, Jia Y, Zhang Y et al. Ubiquitination of UVRAG by SMURF1 promotes autophagosome maturation and inhibits hepatocellular carcinoma growth. Autophagy 2019;15:1130–49.

85 Feng L, Li M, Hu X et al. CK1δ stimulates ubiquitination-dependent proteasomal degradation of ATF4 to promote chemoresistance in gastric Cancer. Clin Trans Med 2021;11:e587.

86 Ferretti LP, Himmels S-F, Trenner A et al. Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to finetune DNA-end resection. Nat Commun 2016;7:1–16.

87 Fierz B, Chatterjee C, McGinty RK et al. Histone H2B ubiquitylation disrupts local and higher-order chromatin compaction. Nat Chem Biol 2011;7:113–9.

88 Finan JD, Leddy HA, Guilak F. Osmotic stress alters chromatin condensation and nucleocytoplasmic transport. Biochem Biophys Res Commun 2011;408:230–5.

89 Finley D, Özkaynak E, Varshavsky A. The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses. Cell 1987;48:1035–46.

90 Fischer DF, van Dijk R, van Tijn P et al. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging 2009;30:847–63.

91 Foresti O, Rodriguez-Vaello V, Funaya C et al. Quality control of inner nuclear membrane proteins by the Asi complex. Science 2014;346:751–5.

92 Fornace AJ, Alamo I, Hollander MC et al. Ubiquftin mRNA is a major stress-induced transcript in mammalian cells. Nucleic Acids Res 1989;17:1215–30.

93 Foster RE, Nnakwe C, Woo L et al. Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun 2006;341:175–83.

94 Fradet-Turcotte A, Canny MD, Escribano-Díaz C et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 2013;499:50–4.

95 Freemont PS, Hanson IM, Trowsdale J. A novel cysteine-rich sequence motif. Cell 1991;64:483–4.

96 French ME, Koehler CF, Hunter T. Emerging functions of branched ubiquitin chains. Cell Discov 2021;7:1–10.

97 Fu Y, Wang H, Dai H et al. OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin. Mol Cell 2021;81:3187–3204.e7.

98 Fujita J. Cold shock response in mammalian cells. J Mol Microbiol Biotechnol 1999;1:243–55.

99 Fukuba H, Takahashi T, Jin HG et al. Abundance of aspargynyl- hydroxylase FIH is regulated by Siah-1 under normoxic conditions. Neurosci Lett 2008;433:209–14.

100 Furukawa M, Xiong Y. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 2005;25:162–71.

101 Galanty Y, Belotserkovskaya R, Coates J et al. RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev 2012;26: 1179–95.

102 Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses to systemic homeostasis. Nat Rev Mol Cell Biol 2018;19:731–45.

103 Gan N, Zhen X, Liu Y et al. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. Nature 2019;572:387–91.

104 Gankam-Kengne F, Couturier BS, Soupart A et al. Osmotic stress–induced defective glial proteostasis contributes to brain demyelination after hyponatremia treatment. J Am Soc Nephrol 2017;28:1802–13.

105 Gao F, Chen D, Si J et al. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet 2015;24:2528–38.

106 Gatti M, Pinato S, Maiolica A et al. RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep 2015;10:226–38.

107 Goldknopf IL, Busch H. Isopeptide linkage between non-histone and histone 2A polypeptides of chromosomal conjugate-protein A24. Proc Natl Acad Sci USA 1977;74:864–8.

108 Graf C, Stankiewicz M, Nikolay R et al. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes. Biochemistry 2010;49:2121–9.

109 Grice GL, Lobb IT, Weekes MP et al. The proteasome distinguishes between heterotypic and homotypic lysine-11-linked polyubiquitin chains. Cell Rep 2015;12:545–53.

110 Gudjonsson T, Altmeyer M, Savic V et al. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell 2012;150:697–709.

111 Guettouche T, Boellmann F, Lane WS et al. Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem 2005;6:1–14.

112 Gwon Y, Maxwell BA, Kolaitis R-M et al. Ubiquitination of G3BP1 mediates stress granule disassembly in a context- specific manner. Science 2021;372:eabf6548.

113 Ha G-H, Ji J-H, Chae S et al. Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double- strand breaks. Nat Commun 2019;10:1–18.

114 Hammel M, Rey M, Yu Y et al. XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double strand break repair. J Biol Chem 2011;286:32638–50.

115 Hanna J, Meides A, Zhang DP et al. A ubiquitin stress response induces altered proteasome composition. Cell 2007;129:747–59.

116 Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell 2020;38:167–97.

117 He Y, Khan S, Huo Z et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J Hematol Oncol 2020;13:1–24.

118 Heath RJ, Goel G, Baxt LA et al. RNF166 determines recruitment of adaptor proteins during antibacterial autophagy. Cell Rep 2016;17:2183–94.

119 Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998;67:425–79.

120 Hindi NN, Elsakrmy N, Ramotar D. The base excision repair process: comparison between higher and lower eukaryotes. Cell Mol Life Sci 2021;78:7943–65.

121 Ho S-R, Mahanic CS, Lee Y-J et al. RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage. Proc Natl Acad Sci USA 2014;111: E2646–55.

122 Hon W-C, Wilson MI, Harlos K et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 2002;417:975–8.

123 Hong M, Li M, Mao C et al. Endoplasmic reticulum stress triggers an acute proteasome-dependent degradation of ATF6. J Cell Biochem 2004;92:723–32.

124 Horn V, Uckelmann M, Zhang H et al. Structural basis of specific H2A K13/K15 ubiquitination by RNF168. Nat Commun 2019;10:1–12.

125 Hromas R, Srinivasan G, Yang M et al. BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1. Iscience 2022;25:105626.

126 Hryciw DH, Ekberg J, Lee A et al. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem 2004;279:P54996–55007.

127 Hu R-G, Sheng J, Qi X et al. The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 2005;437:981–6.

128 Hu R-G, Wang H, Xia Z et al. The N-end rule pathway is a sensor of heme. Proc Natl Acad Sci USA 2008;105:76–81.

129 Huang Y, Sun Y, Cao Y et al. HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation. Cell Death Dis 2017;8:3202.

130 Huen MS, Grant R, Manke I et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 2007;131:901–14.

131 Huibregtse JM, Scheffner M, Beaudenon S et al. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 1995;92:2563–7.

132 Hunkeler M, Jin CY, Fischer ES. Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. Science 2023;379:1105–11.

133 Hwang J, Qi L. Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways. Trends Biochem Sci 2018;43:593–605.

134 In S, Kim Y-I, Lee JE et al. RNF20/40-mediated eEF-1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes. Nucleic Acids Res 2019;47:2840–55.

135 Ishida N, Nakagawa T, Iemura S-I et al. Ubiquitylation of Ku80 by RNF126 promotes completion of nonhomologous end joining-mediated DNA repair. Mol Cell Biol 2017;37:e00347–16.

136 Ismail IH, Gagné J-P, Genois M-M et al. The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat Cell Biol 2015;17:1446–57.

137 Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J 2016;283:2640–52.

138 Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071–8.

139 Jing L, Yao L, Zhao M et al. Organ preservation: from the past to the future. Acta Pharmacol Sin 2018;39:845–57.

140 Joshi S, Singh AR, Durden DL. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem 2014;289:22785–97.

141 Kaiser SE, Riley BE, Shaler TA et al. Protein standard absolute quantification (PSAQ) method for the measurement of cellular ubiquitin pools. Nat Methods 2011;8:691–6.

142 Kalb R, Mallery DL, Larkin C et al. BRCA1 is a histone-H2A-specific ubiquitin ligase. Cell Rep 2014;8:999–1005.

143 Kamynina E, Debonneville C, Bens M et al. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J 2001;15:204–14.

144 Kane LA, Lazarou M, Fogel AI et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 2014;205:143–53.

145 Kaneko M, Iwase I, Yamasaki Y et al. Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation. Sci Rep 2016;6:1–10.

146 Kang HJ, Kim HJ, Rih J-K et al. BRCA1 plays a role in the hypoxic response by regulating HIF-1α stability and by modulating vascular endothelial growth factor expression. J Biol Chem 2006;281:13047–56.

147 Kaplan JH. Biochemistry of na, K-ATPase. Annu Rev Biochem 2002;71:511–35.

148 Karim M, Biquand E, Declercq M et al. Nonproteolytic K29-linked ubiquitination of the PB2 replication protein of influenza A viruses by proviral cullin 4-based E3 ligases. Mbio 2020;11:e00305–20.

149 Kaspar JW, Niture SK, Jaiswal AK. Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 2009;47:1304–9.

150 Kazlauskaite A, Kondapalli C, Gourlay R et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 2014;460:127–39.

151 Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 2006;70:1469–80.

152 Kerscher O, Felberbaum R, Hochstrasser M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol 2006;22:159–80.

153 Khan S, He Y, Zhang X et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 2020;39:4909–24.

154 Khmelinskii A, Blaszczak E, Pantazopoulou M et al. Protein quality control at the inner nuclear membrane. Nature 2014;516:410–3.

155 Kim H, Chen J, Yu X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 2007;316:1202–5.

156 Kim E, Wang B, Sastry N et al. NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Hum Mol Genet 2016;25:211–22.

157 Kimura Y, Tanaka K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J Biochem 2010;147:793–8.

158 Kmiecik SW, Drzewicka K, Melchior F et al. Heat shock transcription factor 1 is SUMOylated in the activated trimeric state. J Biol Chem 2021;296:100324–14.

159 Kobayashi A, Kang M-I, Watai Y et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 2006;26:221–9.

160 Koh MY, Darnay BG, Powis G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1α, leading to its oxygen-independent degradation. Mol Cell Biol 2008;28:7081–95.

161 Kolas NK, Chapman JR, Nakada S et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 2007;318:1637–40.

162 Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans 2009;37:937–53.

163 Koyano F, Okatsu K, Kosako H et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014;510:162–6.

164 Kwasna D, Rehman SAA, Natarajan J et al. Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Mol Cell 2018;70:150–64.e156.

165 Lam YA, Pickart CM, Alban A et al. Inhibition of the ubiquitin-proteasome system in Alzheimer’s disease. Proc Natl Acad Sci USA 2000;97:9902–6.

166 Lando D, Peet DJ, Gorman JJ et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002;16:1466–71.

167 Laroia G, Cuesta R, Brewer G et al. Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 1999;284:499–502.

168 Lassot I, Ségéral E, Berlioz-Torrent C et al. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCFβTrCPUbiquitin ligase. Mol Cell Biol 2001;21:2192–202.

169 Lassot I, Estrabaud E, Emiliani S et al. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. J Biol Chem 2005;280:41537–45.

170 Lee J-H, Paull TT. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005;308:551–4.

171 Lee J-W, Bae S-H, Jeong J-W et al. Hypoxia-inducible factor (HIF-1) α: its protein stability and biological functions. Exp Mol Med 2004;36:1–12.

172 Lee Y, Chou T-F, Pittman SK et al. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep 2017;19:188–202.

173 Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol 2020;21:268–83.

174 Leitch V, Agre P, King LS. Altered ubiquitination and stability of aquaporin-1 in hypertonic stress. Proc Natl Acad Sci USA 2001;98:2894–8.

175 Li C, Han T, Guo R et al. An integrative synthetic biology approach to interrogating cellular ubiquitin and ufm signaling. Int J Mol Sci 2020a;21:4231.

176 Li C, Lu W, Yang L et al. MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3. Natl Sci Rev 2020b;7:671–85.

177 Li J, Cao F, Yin H-l et al. Ferroptosis: past, present and future. Cell Death Dis 2020c;11:1–13.

178 Li C, Han T, Li Q et al. MKRN3-mediated ubiquitination of Poly (A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty. Nucleic Acids Res 2021;49:3796–813.

179 Liao Y, Sumara I, Pangou E. Non-proteolytic ubiquitylation in cellular signaling and human disease. Commun Biol 2022;5:1–15.

180 Linares LK, Hengstermann A, Ciechanover A et al. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci USA 2003;100:12009–14.

181 Liu Z, Chen P, Gao H et al. Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression. Cancer Cell 2014;26:106–20.

182 Liu P, Gan W, Guo C et al. Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair. Mol Cell 2015;57:648–61.

183 Liu J, Zhang C, Zhao Y et al. Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun 2017;8:1–16.

184 Liu L, Damerell DR, Koukouflis L et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinformatics 2019a;35:2882–4.

185 Liu T, Jiang L, Tavana O et al. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res 2019b;79:1913–24.

186 Liu B, Ruan J, Chen M et al. Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases. Mol Psychiatry 2022a;27:259–68.

187 Liu J, Jin J, Liang T et al. To Ub or not to Ub: a regulatory question in TGF-β signaling. Trends Biochem Sci 2022b;47:1059–72.

188 Liu S, Jiang T, Bu F et al. Structural basis for BIRC6 to balance apoptosis and autophagy. bioRxiv 2022c.

189 Lopata A, Kniss A, Löhr F et al. Ubiquitination in the ERAD process. Int J Mol Sci 2020;21:5369.

190 Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012;481:287–94.

191 Lou Z, Minter-Dykhouse K, Franco S et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell 2006;21:187–200.

192 Lu X, Xu M, Zhu Q et al. RNF8-ubiquitinated KMT5A is required for RNF168-induced H2A ubiquitination in response to DNA damage. FASEB J 2021;35:e21326.

193 Luo K, Zhang H, Wang L et al. Sumoylation of MDC1 is important for proper DNA damage response. EMBO J 2012;31:3008–19.

194 Ma B, Chen Y, Chen L et al. Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat Cell Biol 2015;17:95–103.

195 Mabbitt PD, Loreto A, Déry M-A, et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. Nat Chem Biol 2020;16:1227–36.

196 MacGregor DR, Penfield S. Exploring the pleiotropy of hos1. J Exp Bot 2015;66:1661–71.

197 Maeoka Y, Okamoto T, Wu Y et al. Renal medullary tonicity regulates RNF183 expression in the collecting ducts via NFAT5. Biochem Biophys Res Commun 2019a;514:436–42.

198 Maeoka Y, Wu Y, Okamoto T et al. NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells. J Biol Chem 2019b;294:101–15.

199 Mailand N, Bekker-Jensen S, Bartek J et al. Destruction of Claspin by SCFβTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol Cell 2006;23:307–18.

200 Mailand N, Bekker-Jensen S, Faustrup H et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 2007;131:887–900.

201 Mallette FA, Mattiroli F, Cui G et al. RNF8-and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J 2012;31:1865–78.

202 Mandemaker I, van Cuijk L, Janssens RC et al. DNA damage- induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway. Sci Rep 2017;7:1–11.

203 Mansour MA. Ubiquitination: friend and foe in cancer. Int J Biochem Cell Biol 2018;101:80–93.

204 Maréchal A, Li J-M, Ji XY et al. PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Mol Cell 2014;53:235–46.

205 Marei H, Tsai W-TK, Kee Y-S et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature 2022;610:182–9.

206 Martinez A, Lectez B, Ramirez J et al. Quantitative proteomic analysis of Parkin substrates in Drosophila neurons. Mol Neurodegener 2017;12:1–19.

207 Matchkov VV, Krivoi II. Specialized functional diversity and interactions of the Na, K-ATPase. Front Physiol 2016;7:179.

208 Mathur A, Pandey VK, Kakkar P. Activation of GSK3β/β-TrCP axis via PHLPP1 exacerbates Nrf2 degradation leading to impairment in cell survival pathway during diabetic nephropathy. Free Radic Biol Med 2018;120:414–24.

209 Mattiroli F, Penengo L. Histone ubiquitination: an integrative signaling platform in genome stability. Trends Genet 2021;37:566–81.

210 Mattiroli F, Vissers JH, van Dijk WJ et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 2012;150:1182–95.

211 Maxwell PH, Wiesener MS, Chang G-W, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271–5.

212 Maxwell BA, Gwon Y, Mishra A et al. Ubiquitination is essential for recovery of cellular activities after heat shock. Science 2021;372:eabc3593.

213 McCabe JT, Burrell AS. Alterations of AP-1 and CREB protein DNA binding in rat supraoptic and paraventricular nuclei by acute and repeated hyperosmotic stress. Brain Res Bull 2001;55:347–58.

214 McClellan AJ, Laugesen SH, Ellgaard L. Cellular functions and molecular mechanisms of non-lysine ubiquitination. Open Biol 2019;9:190147.

215 McDonald FJ, Western AH, McNeil JD et al. Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na+ channel. Am J Physiol Renal Physiol 2002;283:F431–6.

216 Medicherla B, Goldberg AL. Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins. J Cell Biol 2008;182:663–73.

217 Min J-h, Yang H, Ivan M et al. Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling. Science 2002;296:1886–9.

218 Mohr SM, Bagriantsev SN, Gracheva EO. Cellular, molecular, and physiological adaptations of hibernation: the solution to environmental challenges. Annu Rev Cell Dev Biol 2020;36:315–38.

219 Møller P, Loft S, Lundby C et al. Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans. FASEB J 2001;15:1181–6.

220 Morett E, Bork P. A novel transactivation domain in parkin. Trends Biochem Sci 1999;24:229–31.

221 Morreale FE, Walden H. Types of ubiquitin ligases. Cell 2016;165:248–248.e1.

222 Moyal L, Lerenthal Y, Gana-Weisz M et al. Requirement of ATM-dependent monoubiquitylation of histone H2B for timely repair of DNA double-strand breaks. Mol Cell 2011;41:529–42.

223 Muz B, de la Puente P, Azab F et al. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 2015;3:83.

224 Nakamura K, Kato A, Kobayashi J et al. Regulation of homologous recombination by RNF20-dependent H2B ubiquitination. Mol Cell 2011;41:515–28.

225 Nakayama K, Frew IJ, Hagensen M et al. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia. Cell 2004;117:941–52.

226 Nakayama K, Qi J, Ronai Z. The ubiquitin ligase Siah2 and the hypoxia response. Mol Cancer Res 2009;7:443–51.

227 Nasu J, Murakami K, Miyagawa S et al. E6AP ubiquitin ligase mediates ubiquitin-dependent degradation of peroxiredoxin 1. J Cell Biochem 2010;111:676–85.

228 Neuhofer W. Role of NFAT5 in inflammatory disorders associated with osmotic stress. Curr Genomics 2010;11:584–90.

229 Nguyen AT, Prado MA, Schmidt PJ et al. UBE2O remodels the proteome during terminal erythroid differentiation. Science 2017;357:eaan0218.

230 Nguyen KT, Mun S-H, Yang J et al. The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis. Nat Cell Biol 2022;24:1239–51.

231 Ning S, Luo L, Yu B et al. Structures, functions, and inhibitors of LUBAC and its related diseases. J Leukoc Biol 2022;112:799–811.

232 Nishiyama H, Itoh K, Kaneko Y et al. A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth. J Cell Biol 1997;137:899–908.

233 Nowsheen S, Aziz K, Aziz A et al. L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage. Nat Cell Biol 2018;20:455–64.

234 Nucifora FC, Nucifora LG, Ng C-H et al. Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat Commun 2016;7:1–11.

235 Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Ann Rev Pathol 2015;10:173–94.

236 Ochi T, Blackford AN, Coates J et al. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 2015;347:185–8.

237 Ohh M, Park CW, Ivan M et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nat Cell Biol 2000;2:423–7.

238 Okamoto T, Wu Y, Matsuhisa K et al. Hypertonicity-responsive ubiquitin ligase RNF183 promotes Na, K-ATPase lysosomal degradation through ubiquitination of its β1 subunit. Biochem Biophys Res Commun 2020;521:1030–5.

239 Okatsu K, Oka T, Iguchi M et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun 2012;3:1016.

240 Olsen SK, Lima CD. Structure of a ubiquitin E1-E2 complex: insights to E1-E2 thioester transfer. Mol Cell 2013;49:884–96.

241 Ong G, Logue SE. Unfolding the interactions between endoplasmic reticulum stress and oxidative stress. Antioxidants 2023;12:981.

242 Onishi M, Yamano K, Sato M et al. Molecular mechanisms and physiological functions of mitophagy. EMBO J 2021;40:e104705.

243 Ordureau A, Sarraf SA, Duda DM et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 2014;56:360–75.

244 Orthwein A, Noordermeer SM, Wilson MD et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 2015;528:422–6.

245 Otten EG, Werner E, Crespillo-Casado A et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 2021;594:111–6.

246 Paltoglou S, Roberts B. HIF-1α and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases. Oncogene 2007;26:604–9.

247 Pan F, Zarate J, Bradley TM. A homolog of the E3 ubiquitin ligase Rbx1 is induced during hyperosmotic stress of salmon. Am J Physiol Regul Integr Comp Physiol 2002;282:R1643–53.

248 Pao K-C, Wood NT, Knebel A et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 2018;556:381–5.

249 Parag HA, Raboy B, Kulka RG. Effect of heat shock on protein degradation in mammalian cells: involvement of the ubiquitin system. EMBO J 1987;6:55–61.

250 Park C-W, Ryu K-Y. Cellular ubiquitin pool dynamics and homeostasis. BMB Rep 2014;47:475–82.

251 Paull TT, Gellert M. The 3′ to 5′ exonuclease activity of Mre11 facilitates repair of DNA double-strand breaks. Mol Cell 1998;1:969–79.

252 Peng H, Yang J, Li G et al. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res 2017;27:657–74.

253 Peng H, Yang F, Hu Q et al. The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity. Autophagy 2020;16:698–708.

254 Peschiaroli A, Dorrello NV, Guardavaccaro D et al. SCFβTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol Cell 2006;23:319–29.

255 Petrone P, Asensio JA, Marini CP. Management of accidental hypothermia and cold injury. Curr Probl Surg 2014;51:417–31.

256 Petroski MD, Deshaies RJ. Function and regulation of cullin–RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005;6:9–20.

257 Petrucelli L, Dickson D, Kehoe K et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 2004;13:703–14.

258 Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem 2001;70:503–33.

259 Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 2015;85:257–73.

260 Pietrucha B, Heropolitańska-Pliszka E, Geffers R et al. Clinical and biological manifestation of RNF168 deficiency in two polish siblings. Front Immunol 2017;8:1683.

261 Podhorecka M, Skladanowski A, Bozko P. H2AX phosphorylation: its role in DNA damage response and cancer therapy. J Nucleic Acids 2010;2010:920161.

262 Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 2019;366:818–22.

263 Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med 2014;20:1242–53.

264 Postow L, Funabiki H. An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation. Cell Cycle 2013;12:587–95.

265 Prajapati P, Gohel D, Shinde A et al. TRIM32 regulates mitochondrial mediated ROS levels and sensitizes the oxidative stress induced cell death. Cell Signal 2020;76:109777.

266 Qian S-B, McDonough H, Boellmann F et al. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 2006;440:551–5.

267 Qiu J, Sheedlo MJ, Yu K et al. Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 2016;533:120–4.

268 Qiu J, Yu K, Fei X et al. A unique deubiquitinase that deconjugates phosphoribosyl-linked protein ubiquitination. Cell Res 2017;27:865–81.

269 Rachakonda G, Xiong Y, Sekhar KR et al. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 2008;21:705–10.

270 Ranjan K, Hedl M, Sinha S et al. Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor- induced unfolded protein response. J Clin Invest 2021;131:e145472.

271 Rape M. Ubiquitylation at the crossroads of development and disease. Nat Rev Mol Cell Biol 2018;19:59–70.

272 Reiter KH, Klevit RE. Characterization of RING-between-RING E3 ubiquitin transfer mechanisms. In: Mayor T, Kleiger G (eds.) The Ubiquitin Proteasome System. New York: Springer, 2018, 3–17.

273 Rennie ML, Chaugule VK, Walden H. Modes of allosteric regulation of the ubiquitination machinery. Curr Opin Struct Biol 2020;62:189–96.

274 Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell 2010;40:253–66.

275 Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 2009;10:398–409.

276 Sadowska A, Kameda T, Krupkova O et al. Osmosensing, osmosignalling and inflammation: how intervertebral disc cells respond to altered osmolarity. Eur Cells Mater 2018;36:231–50.

277 Sakamaki J-i, Ode KL, Kurikawa Y et al. Ubiquitination of phosphatidylethanolamine in organellar membranes. Mol Cell 2022;82:3677–3692.e11.

278 Sakamoto KM, Kim KB, Kumagai A et al. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA 2001;98:8554–9.

279 Sánchez-Tena S, Cubillos-Rojas M, Schneider T et al. Functional and pathological relevance of HERC family proteins: a decade later. Cell Mol Life Sci 2016;73:1955–68.

280 Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta, Mol Cell Res 2013;1833:3460–70.

281 Schmidt CK, Galanty Y, Sczaniecka-Clift M et al. Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair. Nat Cell Biol 2015;17:1458–70.

282 Schneider M, Radoux CJ, Hercules A et al. The PROTACtable genome. Nat Rev Drug Discovery 2021;20:789–97.

283 Schödel J, Ratcliffe PJ. Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol 2019;15:641–59.

284 Schofield JH, Schafer ZT. Mitochondrial reactive oxygen species and mitophagy: a complex and nuanced relationship. Antioxid Redox Signal 2021;34:517–30.

285 Schulman BA, Wade Harper J. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 2009;10:319–31.

286 Schwake M, Friedrich T, Jentsch TJ. An internalization signal in ClC-5, an endosomal Cl⁻ channel mutated in Dent’s disease. J Biol Chem 2001;276:12049–54.

287 Sheen MR, Kim J-A, Lim SW et al. Interstitial tonicity controls TonEBP expression in the renal medulla. Kidney Int 2009;75:518–25.

288 Shen Y, Liu W, Zhang X et al. TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages. FASEB J 2020;34:7144–159.

289 Sheng X, You Q, Zhu H et al. Bacterial effector NleL promotes enterohemorrhagic E. coli-induced attaching and effacing lesions by ubiquitylating and inactivating JNK. PLoS Pathog 2017;13:e1006534.

290 Sheng X, You Q, Zhu H et al. Enterohemorrhagic E. coli effector NleL disrupts host NF-κB signaling by targeting multiple host proteins. J Mol Cell Biol 2020;12:318–21.

291 Shi W, Ma Z, Willers H et al. Disassembly of MDC1 foci is controlled by ubiquitin-proteasome-dependent degradation. J Biol Chem 2008;283:31608–16.

292 Shin D, Mukherjee R, Liu Y et al. Regulation of phosphoribosyl- linked serine ubiquitination by deubiquitinases DupA and DupB. Mol Cell 2020;77:164–179.e6.

293 Shirasaki R, Matthews GM, Gandolfi S et al. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep 2021;34:108532.

294 Siednienko J, Jackson R, Mellett M et al. Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3-and viral-induced expression of type I interferons. Nat Immunol 2012;13:1055–62.

295 Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem 2017;86:715–48.

296 Singh S, Ng J, Sivaraman J. Exploring the “Other” subfamily of HECT E3-ligases for therapeutic intervention. Pharmacol Ther 2021;224:107809.

297 So CC, Ramachandran S, Martin A. E3 ubiquitin ligases RNF20 and RNF40 are required for double-stranded break (DSB) repair: evidence for monoubiquitination of histone H2B lysine 120 as a novel axis of DSB signaling and repair. Mol Cell Biol 2019;39:e00488–18.

298 Sobhian B, Shao G, Lilli DR et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 2007;316:1198–202.

299 Sonna LA, Fujita J, Gaffin SL et al. Invited review: effects of heat and cold stress on mammalian gene expression. J Appl Physiol 2002;92:1725–42.

300 Soss SE, Rose KL, Hill S et al. Biochemical and proteomic analysis of ubiquitination of Hsc70 and Hsp70 by the E3 ligase CHIP. PLoS One 2015;10:e0128240.

301 Spit M, Rieser E, Walczak H. Linear ubiquitination at a glance. J Cell Sci 2019;132:jcs208512.

302 Spriggs KA, Bushell M, Willis AE. Translational regulation of gene expression during conditions of cell stress. Mol Cell 2010;40:228–37.

303 Squair DR, Virdee S. A new dawn beyond lysine ubiquitination. Nat Chem Biol 2022;18:802–11.

304 Staub O, Dho S, Henry P et al. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle’s syndrome. EMBO J 1996;15:2371–80.

305 Staub O, Gautschi I, Ishikawa T et al. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J 1997;16:6325–36.

306 Stewart GS, Panier S, Townsend K et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 2009;136:420–34.

307 Stewart MD, Ritterhoff T, Klevit RE et al. E2 enzymes: more than just middle men. Cell Res 2016;26:423–40.

308 Stucki M, Clapperton JA, Mohammad D et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 2005;123:1213–26.

309 Sun H, Li X-B, Meng Y et al. TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis. Cancer Res 2013;73:4950–9.

310 Sun S, Shi G, Sha H et al. IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat Cell Biol 2015;17:1546–55.

311 Sun H, Wei G, Liu H et al. Inhibition of XBP1s ubiquitination enhances its protein stability and improves glucose homeostasis. Metabolism 2020;105:154046.

312 Sun X, Huang N, Li P et al. TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life Sci 2023;321:121608.

313 Swatek KN, Komander D. Ubiquitin modifications. Cell Res 2016;26:399–422.

314 Sy SM, Huen MS, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA 2009;106:7155–60.

315 Takeda K, Nagashima S, Shiiba I et al. MITOL prevents ER stress-induced apoptosis by IRE 1α ubiquitylation at ER–mitochondria contact sites. EMBO J 2019;38:e100999.

316 Tang H, Jiang X, Hua Y et al. NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation. Endocr Connect 2023;12:e220459.

317 Tank EM, True HL. Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates. PLoS Genet 2009;5:e1000382.

318 Thorslund T, Ripplinger A, Hoffmann S et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature 2015;527:389–93.

319 Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed 2016;55:1966–73.

320 Toyofuku T, Okamoto Y, Ishikawa T et al. LRRK 2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK-mediated ubiquitination pathway. EMBO J 2020;39:e100875.

321 Trempe J-F, Sauvé V, Grenier K et al. Structure of Parkin reveals mechanisms for ubiquitin ligase activation. Science 2013;340:1451–5.

322 Trulsson F, Akimov V, Robu M et al. Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates. Nat Commun 2022;13:1–17.

323 Uckelmann M, Sixma TK. Histone ubiquitination in the DNA damage response. DNA Repair (Amst) 2017;56:92–101.

324 Ui A, Nagaura Y, Yasui A. Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair. Mol Cell 2015;58:468–82.

325 Van Der Reijden BA, Erpelinck-Verschueren CA, Löwenberg B et al. TRIADs: a new class of proteins with a novel cysteine-rich signature. Protein Sci 1999;8:1557–61.

326 Van Leeuwen FW, de Kleijn DP, van den Hurk HH et al. Frameshift mutants of β amyloid precursor protein and ubiquitin-B in Alzheimer’s and Down patients. Science 1998;279:242–7.

327 Varshavsky A. The N-end rule pathway and regulation by proteolysis. Protein Sci 2011;20:1298–345.

328 Vijay-Kumar S, Bugg CE, Cook WJ. Structure of ubiquitin refined at 1.8 Å resolution. J Mol Biol 1987;194:531–44.

329 Walser F, Mulder MP, Bragantini B et al. Ubiquitin phosphorylation at Thr12 modulates the DNA damage response. Mol Cell 2020;80:423–436.e9.

330 Walters B, Campbell S, Chen P et al. Differential effects of Usp14 and Uch-L1 on the ubiquitin proteasome system and synaptic activity. Mol Cell Neurosci 2008;39:539–48.

331 Wan M, Sulpizio AG, Akturk A et al. Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase- domain–containing Legionella effectors. Proc Natl Acad Sci USA 2019;116:23518–26.

332 Wang B, Elledge SJ. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 2007;104:20759–63.

333 Wang GL, Jiang B-H, Rue EA et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510–4.

334 Wang H, Zhai L, Xu J et al. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell 2006;22:383–94.

335 Wang B, Matsuoka S, Ballif BA et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 2007;316:1194–8.

336 Wang Y, Yang C, Nahla Abdalla Hassan E et al. HO-1 reduces heat stress-induced apoptosis in bovine granulosa cells by suppressing oxidative stress. Aging (Albany NY) 2019;11:5535.

337 Wang P, Dai X, Jiang W et al. RBR E3 ubiquitin ligases in tumorigenesis. Semin Cancer Biol 2020a;67:131–44.

338 Wang Y, Argiles-Castillo D, Kane EI et al. HECT E3 ubiquitin ligases–emerging insights into their biological roles and disease relevance. J Cell Sci 2020b;133:jcs228072.

339 Wang H-P, Chen W-J, Shen J-M et al. Attenuating glucose metabolism by Fbxw7 promotes Taxol sensitivity of colon cancer cells through downregulating NADPH oxidase 1 (Nox1). Ann Trans Med 2021;9:886.

340 Wang C-C, Peng H, Wang Z et al. TRIM72-mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells. Mil Med Res 2022a;9:1–4.

341 Wang Y-T, Liu T-Y, Shen C-H et al. K48/K63-linked polyubiquitination of ATG9A by TRAF6 E3 ligase regulates oxidative stress-induced autophagy. Cell Rep 2022b;38:110354.

342 Wang Y, Wang S, Zhang W. HRD1 functions as a tumor suppressor in ovarian cancer by facilitating ubiquitination- dependent SLC7A11 degradation. Cell Cycle 2023;22:1116–26.

343 Weber J, Polo S, Maspero E. HECT E3 ligases: a tale with multiple facets. Front Physiol 2019;10:370.

344 Wei P, Pan D, Mao C et al. RNF34 is a cold-regulated E3 ubiquitin ligase for PGC-1α and modulates brown fat cell metabolism. Mol Cell Biol 2012;32:266–75.

345 Weissman AM. Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2001;2:169–78.

346 Wilson MD, Benlekbir S, Fradet-Turcotte A et al. The structural basis of modified nucleosome recognition by 53BP1. Nature 2016;536:100–3.

347 Wolyniec K, Levav-Cohen Y, Jiang Y et al. The E6AP E3 ubiquitin ligase regulates the cellular response to oxidative stress. Oncogene 2013;32:3510–9.

348 Wu X, Rapoport TA. Mechanistic insights into ER-associated protein degradation. Curr Opin Cell Biol 2018;53:22–8.

349 Wu D, Rastinejad F. Structural characterization of mammalian bHLH-PAS transcription factors. Curr Opin Struct Biol 2017;43:1–9.

350 Wu W, Sato K, Koike A et al. HERC2 is an E3 ligase that targets BRCA1 for degradation. Cancer Res 2010;70:6384–92.

351 Wu J, Zhang X, Zhang L et al. Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol Cell 2012;46:351–61.

352 Wu Y, Jiao H, Yue Y et al. Ubiquitin ligase E3 HUWE1/MULE targets transferrin receptor for degradation and suppresses ferroptosis in acute liver injury. Cell Death Differ 2022;29:1705–18.

353 Wu-Baer F, Lagrazon K, Yuan W et al. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem 2003;278:34743–6.

354 Xia Y, Wang J, Xu S et al. MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Mol Cell Biol 2007;27:510–7.

355 Xie Y, Hou W, Song X et al. Ferroptosis: process and function. Cell Death Differ 2016;23:369–79.

356 Xu P, Duong DM, Seyfried NT et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 2009;137:133–45.

357 Yan Q, Dutt S, Xu R et al. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol Cell 2009;36:110–20.

358 Yanagitani K, Juszkiewicz S, Hegde RS. UBE2O is a quality control factor for orphans of multiprotein complexes. Science 2017;357:472–5.

359 Yang S, Wang B, Humphries F et al. The E3 ubiquitin ligase Pellino3 protects against obesity-induced inflammation and insulin resistance. Immunity 2014;41:973–87.

360 Yang Y, Luo M, Zhang K et al. Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun 2020;11:433.

361 Yang E, Huang S, Jami-Alahmadi Y et al. Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes. PLoS Pathog 2022;18:e1010743.

362 Yasuda S, Tsuchiya H, Kaiho A et al. Stress- and ubiquitylation- dependent phase separation of the proteasome. Nature 2020;578:296–300.

363 Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 2009;10:755–64.

364 Yin Y, Seifert A, Chua JS et al. SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev 2012;26:1196–208.

365 Yonashiro R, Sugiura A, Miyachi M et al. Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation. Mol Biol Cell 2009;20:4524–30.

366 Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011;12:9–14.

367 Yu X, Fu S, Lai M et al. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 2006;20:1721–6.

368 Yuan J, Lv T, Yang J et al. HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox Biol 2022;58:102546.

369 Zeng M, Xiong Y, Safaee N et al. Exploring targeted degradation strategy for oncogenic KRASG12C. Cell Chem Biol 2020;27:19–31.e6.

370 Zhang F, Ma J, Wu J et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 2009;19:524–9.

371 Zhang H, Amick J, Chakravarti R et al. A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. Structure 2015;23:472–82.

372 Zhang Q, Karnak D, Tan M et al. FBXW7 facilitates nonhomologous end-joining via K63-linked polyubiquitylation of XRCC4. Mol Cell 2016;61:419–33.

373 Zhang W, Jiang B, Liu Y et al. Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4. Free Radic Biol Med 2022;180:75–84.

374 Zhang J, Xie H, Yao J et al. TRIM59 promotes steatosis and ferroptosis in non-alcoholic fatty liver disease via enhancing GPX4 ubiquitination. Hum Cell 2023;36:209–22.

375 Zhao S, El-Deiry WS. Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase. Oncotarget 2021;12:1970–9.

376 Zhao W, Steinfeld JB, Liang F et al. BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 2017;550:360–5.

377 Zheng J, Chang L, Bao X et al. TRIM21 drives intervertebral disc degeneration induced by oxidative stress via mediating HIF-1α degradation. Biochem Biophys Res Commun 2021;555:46–53.

378 Zhou Q, Zhang J. K27-linked noncanonic ubiquitination in immune regulation. J Leukoc Biol 2022;111:223–35.

379 Zhou W, Xu J, Tan M et al. UBE2M is a stress-inducible dual E2 for neddylation and ubiquitylation that promotes targeted degradation of UBE2F. Mol Cell 2018;70:1008–1024.e6.

380 Zhu X, Zhang J, Sun H et al. Ubiquitination of inositol-requiring enzyme 1 (IRE1) by the E3 ligase CHIP mediates the IRE1/TRAF2/JNK pathway. J Biol Chem 2014;289:30567–77.

381 Zhu T, Liu B, Wu D et al. Autophagy regulates VDAC3 ubiquitination by FBXW7 to promote erastin-induced ferroptosis in acute lymphoblastic leukemia. Front Cell Dev Biol 2021a;9:740884.

382 Zhu Y, Zhang C, Huang M et al. TRIM26 induces ferroptosis to inhibit hepatic stellate cell activation and mitigate liver fibrosis through mediating SLC7A11 ubiquitination. Front Cell Dev Biol 2021b;9:644901.

383 Zhu X, Xue J, Jiang X et al. TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination. Nucleic Acids Res 2022;50:1517–30.