The emerging roles of UFMylation in the modulation of immune responses

Abstract

Post-translational modification is a rite of passage for cellular functional proteins and ultimately regulate almost all aspects of life. Ubiquitin-fold modifier 1 (UFM1) system represents a newly identified ubiquitin-like modification system with indispensable biological functions, and the underlying biological mechanisms remain largely undiscovered. The field has recently experienced a rapid growth of research revealing that UFMylation directly or indirectly regulates multiple immune processes. Here, we summarised important advances that how UFMylation system responds to intrinsic and extrinsic stresses under certain physiological or pathological conditions and safeguards immune homeostasis, providing novel perspectives into the regulatory framework and functions of UFMylation system, and its therapeutic applications in human diseases.

Keywords

immune homeostasis / post-translational modifications / UFM1 / UFMylation

References

[1] Paludan S, Pradeu T, Masters S, Mogensen TH. Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat Rev Immunol. 2021; 21(3): 137-150.

[2] Madiraju C, Novack JP, Reed JC, Matsuzawa SI. K63 ubiquitination in immune signaling. Trends Immunol. 2022; 43(2): 148-162.

[3] Sampson C, Wang Q, Otkur W, et al. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clin Transl Med. 2023; 13(3): e1204.

[4] Komatsu M, Chiba T, Tatsumi K, et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 2004; 23(9): 1977-1986.

[5] Zhou X, Mahdizadeh SJ, Le Gallo M, Eriksson LA, Chevet E, Lafont E. UFMylation: a ubiquitin-like modification. Trends Biochem Sci. 2024; 49(1): 52-67.

[6] Komatsu M, Inada T, Noda NN. The UFM1 system: working principles, cellular functions, and pathophysiology. Mol Cell. 2024; 84(1): 156-169.

[7] Snider DL, Parka M, Murphya KA, Beachboarda DC, Horner SM. Signaling from the RNA sensor RIG-I is regulated by UFMylation. Proc Natl Acad Sci U S A. 2022; 119(15): e2119531119.

[8] Yiu SPT, Zerbe C, Vanderwall D, Huttlin EL, Weekes MP, Gewurz BE. An Epstein–Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation. Mol Cell. 2023; 83(13): 2367-2386.

[9] Tao Y, Yin S, Liu Y, et al. UFL1 promotes antiviral immune response by maintaining STING stability independent of UFMylation. Cell Death Differ. 2023; 30(1): 16-26.

[10] Zhoua J, Maa X, Heb X, et al. Dysregulation of PD-L1 by UFMylation imparts tumour immune evasion and identified as a potential therapeutic target. Proc Natl Acad Sci U S A. 2023; 120(11): e2215732120.

[11] He C, Xing X, Chen HY, et al. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumour immunity. Mol Cell. 2024; 84(6): 1120-1138. e8.

[12] Zhu H, Bhatt B, Sivaprakasam S, et al. Ufbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR. Nat Commun. 2019; 10(1): 1084.

[13] Balce DR, Wang Y-T, McAllaster MR, et al. UFMylation inhibits the proinflammatory capacity of interferon-γ–activated macrophages. Proc Natl Acad Sci U S A. 2021; 118(1): e2011763118.

[14] Wang J, An H, Mayo MW, Baldwin AS, Yarbrough WG. LZAP, a putative tumor suppressor, selectively inhibits NF-κB. Cancer Cell. 2007; 12(3): 239-251.

[15] Li C, Wang X, Kuang M, et al. UFL1 modulates NLRP3 inflammasome activation and protects against pyroptosis in LPS-stimulated bovine mammary epithelial cells. Mol Immunol. 2019; 112: 1-9.

[16] Cai Y, Zhu G, Liu S, et al. Indispensable role of the ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation. Cell Discov. 2019; 5: 7.

[17] Hu X, Zhang H, Zhuang L, et al. Ubiquitin-fold modifier-1 participates in the diabetic inflammatory response by regulating NF-κB p65 nuclear translocation and the ubiquitination and degradation of IκBα. Drug Des Devel Ther. 2020; 25(14): 795-810.

[18] Pang Q, Xiong J, Hu X-L, et al. UFM1 protects macrophages from oxLDL-induced foam cell formation through a liver X receptor α dependent pathway. J Atheroscler Thromb. 2015; 22(11): 1124-1140.

[19] Su M, Yue Z, Wang H, et al. UFMylation is activated in vascular remodeling and lipopolysaccharide-induced endothelial cell injury. DNA Cell Biol. 2018; 37(5): 426-431.

[20] Ha BH, Ahn HC, Kang SH, Tanaka K, Fau CC, Kim EE. Structural basis for Ufm1 processing by UfSP1. J Biol Chem. 2008; 283(21): 14893-14900.

[21] Liang Q, Jin Y, Xu S, et al. Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease. J Biol Chem. 2022; 298(6): 102016.

[22] Kang SH, Tatsumi K, Kim GR, et al. Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2. J Biol Chem. 2007; 282(8): 5256-5262.

[23] Millrine D, Cummings T, Matthews SP, et al. Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation. Cell Rep. 2022; 40(5): 111168.

[24] Ha BH, Yj J, Sc S, et al. Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J Biol Chem. 2011; 286(12): 10248-10257.

[25] Liu G, Forouhar F, Eletsky A, et al. NMR and x-ray structures of human E2-like ubiquitin-fold modifier conjugating enzyme 1 (UFC1) reveal structural and functional conservation in the metazoan UFM1-UBA5-UFC1 ubiquitination pathway. J Struct Funct Genomics. 2009; 10(2): 127-136.

[26] Tatsumi K, Sou Y-S, Tada N, et al. A novel type of E3 ligase for the Ufm1 conjugation system. J Biol Chem. 2010; 285(8): 5417-5427.

[27] Yoo Hee M, Kang Sung H, Kim Jae Y, et al. Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development. Mol Cell. 2014; 56(2): 261-274.

[28] Liang JR, Lingeman E, Luong T, et al. A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation. Cell. 2020; 180(6): 1160-1177. e20.

[29] Grimes HL, Cai Y, Pi W, et al. UFBP1, a key component of the Ufm1 conjugation system, is essential for UFMylation-mediated regulation of erythroid development. PLoS Genet. 2015; 11(11): e1005643.

[30] Peter JJ, Magnussen HM, DaRosa PA, et al. A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation. EMBO J. 2022; 41(21): e111015.

[31] Yang R, Wang H, Kang B, et al. CDK5RAP3, a UFL1 substrate adaptor, is critical for liver development. Development. 2019; 146(2): dev169235.

[32] Walczak CP, Leto DE, Zhang L, et al. Ribosomal protein RPL26 is the principal target of UFMylation. Proc Natl Acad Sci U S A. 2019; 116(4): 1299-1308.

[33] Wu J, Lei G, Mei M, Tang Y, Li H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing protein 1 (DDRGK1) and modulates NF-κB signaling. J Biol Chem. 2010; 285(20): 15126-15136.

[34] Jiang H, Luo S, Li H. Cdk5 activator-binding protein C53 regulates apoptosis induced by genotoxic stress via modulating the G2/M DNA damage checkpoint. J Biol Chem. 2005; 280(21): 20651-20659.

[35] Dai YF, Lin N, He DQ, et al. LZAP promotes the proliferation and invasiveness of cervical carcinoma cells by targeting AKT and EMT. J Cancer. 2020; 11(6): 1625-1633.

[36] Egusquiaguirre SP, Liu S, Tošić I, et al. CDK5RAP3 is a co-factor for the oncogenic transcription factor STAT3. Neoplasia. 2020; 22(1): 47-59.

[37] Chisholm AD, Chen C, Itakura E, Weber KP, Hegde RS, de Bono M. An ER complex of ODR-4 and ODR-8/Ufm1 specific protease 2 promotes GPCR maturation by a Ufm1-independent mechanism. PLoS Genet. 2014; 10(3): e1004082.

[38] Xu X, Huang W, Bryant C, Dong Z, Li H, Wu G. The UFMylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER. Sci Adv. 2024; 10(25): eadm9216.

[39] Muona M, Ishimura R, Laari A, et al. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am J Hum Genet. 2016; 99(3): 683-694.

[40] Nahorski MS, Maddirevula S, Ishimura R, et al. Biallelic UFM1 and UFC1 mutations expand the essential role of UFMylation in brain development. Brain. 2018; 141(7): 1934-1945.

[41] Li X-J, Duan R, Shi Y, et al. UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia. PLoS One. 2016; 11(2): e0149039.

[42] Di Rocco M, Rusmini M, Caroli F, et al. Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation. Clin Genet. 2018; 93(3): 671-674.

[43] Egunsola AT, Bae Y, Jiang M-M, et al. Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J Clin Invest. 2017; 127(4): 1475-1484.

[44] Zhang M, Zhu X, Zhang Y, et al. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ. 2015; 22(12): 1922-1934.

[45] Tatsumi K, Yamamoto-Mukai H, Shimizu R, et al. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nat Commun. 2011; 2(1): 181.

[46] Liu D, Wd W, Db M, et al. Tumor suppressor Lzap regulates cell cycle progression, doming, and zebrafish epiboly. Dev Dyn. 2011; 240(6): 1613-1625.

[47] Li J, Yue G, Ma W, et al. Ufm1-specific ligase Ufl1 regulates endoplasmic reticulum homeostasis and protects against heart failure. Circ Heart Fail. 2018; 11(10): e004917.

[48] DaRosa P, Penchev I, Gumbin S, et al. UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER. Nature. 2024; 627(8003): 445-452.

[49] Makhlouf L, Peter JJ, Magnussen HM, et al. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature. 2024; 627(8003): 437-444.

[50] Scavonea F, Gumbinb SC, Rosaa PAD, Kopito RR. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2023; 120(16): e2220340120.

[51] Wang L, Xu Y, Rogers H, et al. UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis. Cell Res. 2020; 30(1): 5-20.

[52] Wang L, Xu Y, Yun S, Yuan Q, Satpute-Krishnan P, Ye Y. SAYSD1 senses UFMylated ribosome to safeguard co-translational protein translocation at the endoplasmic reticulum. Cell Rep. 2023; 42(1): 112028.

[53] Endo R, Chen YK, Burke J, et al. Dysregulation of ribosome-associated quality control elicits cognitive disorders via overaccumulation of TTC3. Proc Natl Acad Sci U S A. 2023; 120(12): e2211522120.

[54] Ishimura R, El-Gowily AH, Noshiro D, et al. The UFM1 system regulates ER-phagy through the UFMylation of CYB5R3. Nat Commun. 2022; 13(1): 7857.

[55] Picchianti L, Sánchez de Medina Hernández V, Zhan N, et al. Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy. EMBO J. 2023; 42(10): e112053.

[56] Stephani M, Picchianti L, Gajic A, et al. A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress. eLife. 2020; 9: e58396.

[57] Liu J, Guan D, Dong M, et al. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nat Cell Biol. 2020; 22(9): 1056-1063.

[58] Qin B, Yu J, Nowsheen S, et al. UFL1 promotes histone H4 UFMylation and ATM activation. Nat Commun. 2019; 10(1): 1242.

[59] Lee L, Oliva ABP, Martinez-Balsalobre E, et al. UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival. Sci Adv. 2021; 7(39): eabc7371.

[60] Wang Z, Gong Y, Peng B, et al. MRE11 UFMylation promotes ATM activation. Nucleic Acids Res. 2019; 47(8): 4124-4135.

[61] Gong Y, Wang Z, Zong W, et al. PARP1 UFMylation ensures the stability of stalled replication forks. Proc Natl Acad Sci U S A. 2024; 121(18): e2322520121.

[62] Tian T, Chen J, Zhao H, et al. UFL1 triggers replication fork degradation by MRE11 in BRCA1/2-deficient cells. Nat Chem Biol. 2024.

[63] Mao M, Chen Y, Yang J, et al. Modification of PLAC8 by UFM1 affects tumorous proliferation and immune response by impacting PD-L1 levels in triple-negative breast cancer. J Immunother Cancer. 2022; 10(12): e005668.

[64] Wang K, Chen S, Wu Y, et al. The UFMylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma. Cell Death Dis. 2023; 14(6): 350.

[65] Zhu J, Ma X, Jing Y, et al. P4HB UFMylation regulates mitochondrial function and oxidative stress. Free Radic Biol Med. 2022; 188: 277-286.

[66] Qin B, Yu J, Nowsheen S, Zhao F, Wang L, Lou Z. STK38 promotes ATM activation by acting as a reader of histone H4 UFMylation. Sci Adv. 2020; 6(23): eaax8214.

[67] Tan Q, Xu X. PTIP UFMylation promotes replication fork degradation in BRCA1-deficient cells. J Biol Chem. 2024; 300(6): 107312.

[68] Yoo HM, Park JH, Kim JY, Chung CH. Modification of ERα by UFM1 increases its stability and transactivity for breast cancer development. Mol Cells. 2022; 46(4): 256-257.

[69] Yang J, Zhou Y, Xie S, et al. Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res. 2021; 40(1): 206.

[70] Shi C, Wang Y, Guo Y, Chen Y, aN Liu. Cooperative down-regulation of ribosomal protein L10 and NF-κB signalling pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells. Oncotarget. 2017; 8(21): 35009-35018.

[71] Casanova J-L, MacMicking JD, Nathan CF. Interferon-γ and infectious diseases: lessons and prospects. Science. 2024; 384(6693): eadl2016.

[72] Rehwinkel J, Gack MU. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020; 20(9): 537-551.

[73] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455(7213): 674-678.

[74] Li W, Lin Y, Wang X, et al. Chicken UFL1 restricts avian influenza virus replication by disrupting the viral polymerase complex and facilitating type I IFN production. J Immunol. 2024; 212(9): 1479-1492.

[75] McAllaster MR, Bhushan J, Balce DR, et al. Autophagy gene-dependent intracellular immunity triggered by interferon-γ. mBio. 2023; 14(6): e0233223.

[76] Kulsuptrakul J, Wang R, Meyers NL, Ott M, Puschnik AS. A genome-wide CRISPR screen identifies UFMylation and TRAMP-like complexes as host factors required for hepatitis A virus infection. Cell Rep. 2021; 34(11): 108859.

[77] Li Y-Y, Zhang G-Y, He J-P, et al. Ufm1 inhibits LPS-induced endothelial cell inflammatory responses through the NF-κB signalling pathway. Int J Mol Med. 2017; 39(5): 1119-1126.

[78] Wang Z, Huang S, Xue Z, et al. UFM1 inhibits the activation of the pyroptosis in LPS-induced goat endometritis. Theriogenology. 2023; 196: 50-58.

[79] Yang G, Wang Y, Chen Y, Huang R. UFL1 attenuates IL-1β-induced inflammatory response in human osteoarthritis chondrocytes. Int Immunopharmacol. 2020; 81: 106278.

[80] Xi P, Ding D, Zhou J, Wang M, Cong YS. DDRGK1 regulates NF-κB activity by modulating IκBα stability. PLoS One. 2013; 8(5): e64231.

[81] Takeuchi T, Nakanishi Y, Ohno H. Microbial metabolites and gut immunology. Annu Rev Immunol. 2024; 42(1): 153-178.

[82] Lam N, Lee Y, Farber DL. A guide to adaptive immune memory. Nat Rev Immunol. 2024. doi:10.1038/s41577-024-01040-6

[83] Zhong T, Lei K, Lin X, et al. Protein ubiquitination in T cell development. Front Immunol. 2022; 13: 941962.

[84] Zhang T, Sun J, Cheng J, et al. The role of ubiquitinase in B cell development and function. J Leukoc Biol. 2021; 109(2): 395-405.

[85] Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019; 2(5): e192535.

[86] Pishesha N, Harmand TJ, Ploegh H. A guide to antigen processing and presentation. Nat Rev Immunol. 2022; 22(12): 751-764.

[87] Liu J, Wang Y, Song L, et al. A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability. Nat Commun. 2017; 8: 14186.

[88] ABC S, IGJ B, EM B, et al. The UFM1 pathway impacts HCMV US2-mediated degradation of HLA class I. Molecules. 2021; 26(2): 287.

[89] Chakraborty B, Byemerwa J, Krebs T, Lim F, Chang CY, McDonnell D. Estrogen receptor signaling in the immune system. Endocr Rev. 2023; 44(1): 117-141.

[90] Yong J, Johnson JD, Arvan P, Han J, Kaufman RJ. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus. Nat Rev Endocrinol. 2021; 17(8): 455-467.

[91] Li J, Tang X, Tu X, et al. UFL1 alleviates ER stress and apoptosis stimulated by LPS via blocking the ferroptosis pathway in human granulosa-like cells. Cell Stress Chaperones. 2022; 27(5): 485-497.

[92] Tang X, Dong H, Fang Z, et al. Ubiquitin-like modifier 1 ligating enzyme 1 relieves cisplatin-induced premature ovarian failure by reducing endoplasmic reticulum stress in granulosa cells. Reprod Biol Endocrinol. 2022; 20(1): 84.

[93] Qiu L, Zheng X, Jaishankar D, et al. Beyond UPR: cell-specific roles of ER stress sensor IRE1α in kidney ischemic injury and transplant rejection. Kidney Int. 2023; 104(3): 463-469.

[94] Zhou Y, Ye X, Zhang C, et al. Ufl1 deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis. J Genet Genomics. 2021; 48(5): 403-410.

[95] Campbell JE, Newgard C. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol. 2021; 22(2): 142-158.

[96] Meurs EF, Lemaire K, Moura RF, et al. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS One. 2011; 6(4): e18517.

[97] Chen F, Sheng L, Zhou T, et al. Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signalling. J Exp Clin Cancer Res. 2023; 42(1): 110.

[98] Zhou J, Ma X, Xu L, et al. Genomic profiling of the UFMylation family genes identifies UFSP2 as a potential tumour suppressor in colon cancer. Clin Transl Med. 2021; 11(12): e642.

[99] Roberts AM, Miyamoto DK, Huffman TR, et al. Chemoproteomic screening of covalent ligands reveals UBA5 as a novel pancreatic cancer target. ACS Chem Biol. 2017; 12(4): 899-904.

[100] da Silva SR, Paiva SL, Bancerz M, et al. A selective inhibitor of the UFM1-activating enzyme, UBA5. Bioorg Med Chem Lett. 2016; 26(18): 4542-4547.

[101] Ishimura R, Ito S, Mao G, et al. Mechanistic insights into the roles of the UFM1 E3 ligase complex in UFMylation and ribosome-associated protein quality control. Sci Adv. 2023; 9(33): eadh3635.

[102] Banerjee S, Varga JK, Kumar M, et al. Structural study of UFL1-UFC1 interaction uncovers the role of UFL1 N-terminal helix in UFMylation. EMBO Rep. 2023; 24(12): e56920.

[103] Xu D, Zhang D, Wei W, Zhang C. UBA5 inhibition restricts lung adenocarcinoma via blocking macrophage M2 polarization and cisplatin resistance. Exp Cell Res. 2024; 440(2): 114148.

[104] Wei Y, Xu X. UFMylation: a unique & fashionable modification for life. Genomics Proteomics Bioinformatics. 2016; 14(3): 140-146.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.