Manipulating autophagic degradation in human diseases: from mechanisms to interventions

Abstract

Targeted degradation, having emerged as a powerful and promising strategy in drug discovery in the past two decades, has provided a solution for many once undruggable targets involved in various diseases. While earlier targeted degradation tools, as exemplified by PROteolysis-TArgeting Chimera (PROTAC), focused on harnessing the ubiquitin-proteasome system, novel approaches that aim to utilize autophagy, a potent, lysosome-dependent degradation pathway, have also surfaced recently as promising modalities. In this review, we first introduce the mechanisms that establish selectivity in autophagy, which provides the rationales for autophagy-based targeted degradation; we also provide an overview on the panoply of cellular machinery involved in this process, an arsenal that could be potentially harnessed. On this basis, we propose four strategies for designing autophagy-based targeted degraders, including Tagging Targets, Directly Engaging Targets, Initiating Autophagy at Targets, and Phagophore-Tethering to Targets. We introduce the current frontiers in this field, including AUtophagy-TArgeting Chimera (AUTAC), Targeted Protein Autophagy (TPA), AUTOphagy-TArgeting Chimera (AUTOTAC, not to be confused with AUTAC), AuTophagosome TEthering Compound (ATTEC), and other experimental approaches as case studies for each strategy. Finally, we put forward a workflow for generating autophagy-based degraders and some important questions that may guide and inspire the process.

Keywords

design strategy / selective autophagy / targeted degradation

References

[1] PaivaSL, CrewsCM. Targeted protein degradation: elements of PROTAC design. Curr Opin Chem Biol 2019;50:111–19.

[2] PetterssonM, CrewsCM. PROteolysis TArgeting Chimeras (PROTACs) - past, present and future. Drug Discov Today Technol 2019;31:15–27.

[3] GuS, CuiD, ChenX, et al. PROTACs: an emerging targeting technique for protein degradation in drug discovery. BioEssays 2018;401700247.

[4] SamarasingheKTG, CrewsCM. Targeted protein degradation: a promise for undruggable proteins. Cell Chem Biol 2021;28:934–51.

[5] ToureM, CrewsCM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed Engl 2016;55:1966–73.

[6] NeklesaTK, Winkler JD, CrewsCM. Targeted protein degradation by PROTACs. Pharmacol Ther 2017;174:138–44.

[7] LinJ, JinJ, ShenY, et al. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics 2021;11:8337–49.

[8] BondMJ, CrewsCM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem Biol 2021;2:725–42.

[9] BékésM, Langley DR, CrewsCM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 2022;21:181–200.

[10] LaiAC, CrewsCM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 2017;16:101–14.

[11] BurslemGM, CrewsCM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 2020;181:102–14.

[12] AnS, FuL. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine 2018;36:553–62.

[13] TroupRI, FallanC, BaudMGJ. Current strategies for the design of PROTAC linkers: a critical review. Explor Target Antitumor Ther 2020;1:273–312.

[14] VarshavskyA. The ubiquitin system, autophagy, and regulated protein degradation. Annu Rev Biochem 2017;86:123–28.

[15] SchneiderM, RadouxCJ, HerculesA, et al. The PROTACtable genome. Nat Rev Drug Discov 2021;20:789–97.

[16] WangY, JiangX, FengF, et al. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B 2020;10:207–38.

[17] BurslemGM, SmithBE, LaiAC, et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem Biol 2018;25:67–77 e63.

[18] CrommPM, Samarasinghe KTG, HinesJ, et al. Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J Am Chem Soc 2018;140:17019–26.

[19] GaoH, ZhengC, DuJ, et al. FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice. Protein Cell 2020;11:534–9.

[20] BondesonDP, MaresA, SmithIE, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol 2015;11:611–7.

[21] MaresA, MiahAH, SmithIED, et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun Biol 2020;3:140.

[22] YouI, Erickson EC, DonovanKA, et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem Biol 2020;27:66–73.e7.e67.

[23] TomoshigeS, NomuraS, OhganeK, et al. Discovery of small molecules that induce the degradation of huntingtin. Angew Chem Int Ed Engl 2017;56:11530–3.

[24] WangW, ZhouQ, JiangT, et al. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics 2021;11:5279–95.

[25] DegerJM, GersonJE, KayedR. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 2015;14:715–24.

[26] CliffeR, SangJC, KundelF, et al. Filamentous aggregates are fragmented by the proteasome holoenzyme. Cell Rep 2019;26:2140–9.e3.e2143.

[27] CiechanoverA, KwonYT. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 2015;47:e147–e147.

[28] GalvesM, RathiR, PragG, et al. Ubiquitin signaling and degradation of aggregate-prone proteins. Trends Biochem Sci 2019;44:872–84.

[29] ThibaudeauTA, Anderson RT, SmithDM. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat Commun 2018;9:1097.

[30] LiZ, ZhuC, DingY, et al. ATTEC: a potential new approach to target proteinopathies. Autophagy 2020;16:185–7.

[31] IzzoA, MolloN, NittiM, et al. Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets. Mol Med 2018;24:2.

[32] TakahashiD, Moriyama J NakamuraT, et al. AUTACs: cargo-specific degraders using selective autophagy. Mol Cell 2019;76:797–810. e10.e710.

[33] NoratP, Soldozy S, Sokolowski, et al. Mitochondrial dysfunction in neurological disorders: exploring mitochondrial transplantation. npj Regen Med 2020;5:22.

[34] LiH-Y, PengZ-G. Targeting lipophagy as a potential therapeutic strategy for nonalcoholic fatty liver disease. Biochem Pharmacol 2022;197:114933.

[35] ErcoliG, Fernandes VE, ChungWY, et al. Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia. Nat Microbiol 2018;3:600–10.

[36] DereticV. Autophagy in tuberculosis. Cold Spring Harb Perspect Med 2014;4:a018481.

[37] PaikS, KimJK, ChungC, et al. Autophagy: a new strategy for host-directed therapy of tuberculosis. Virulence 2019;10:448–59.

[38] SharmaV, VermaS, SeranovaE, et al. Selective autophagy and xenophagy in infection and disease. Front Cell Dev Biol 2018;6:147.

[39] DingY, FeiY, LuB. Emerging new concepts of degrader technologies. Trends Pharmacol Sci 2020;41:464–74.

[40] TakahashiD, Arimoto H. Selective autophagy as the basis of autophagy- based degraders. Cell Chem Biol 2021;28:1061–71.

[41] AlabiS, CrewsC. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J Biol Chem 2021;296:100647.

[42] PeiJ, WangG, FengL, et al. Targeting lysosomal degradation pathways: new strategies and techniques for drug discovery. J Med Chem 2021;64:3493–507.

[43] BonamSR, WangF, MullerS. Lysosomes as a therapeutic target. Nat Rev Drug Discov 2019;18:923–48.

[44] KocakM, Ezazi Erdi S, JorbaG, et al. Targeting autophagy in disease: established and new strategies. Autophagy 2022;18:473–95.

[45] YimWW, Mizushima N. Lysosome biology in autophagy. Cell Discov 2020;6:6.

[46] BanikSM, PedramK, WisnovskyS, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 2020;584:291–7.

[47] AhnG, BanikSM, MillerCL, et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Bio, 2021;17:937–46.

[48] CottonAD, NguyenDP, GramespacherJA, et al. Development of antibody-based PROTACs for the degradation of the cell-Surface immune checkpoint protein PD-L1. J Am Chem Soc 2021;143:593–8.

[49] CaianielloDF, ZhangM, RayJD, et al. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat Chem Biol 2021;17:947–53.

[50] CassidyK, ZhaoH. Redefining the scope of targeted protein degradation: translational opportunities in hijacking the autophagy-lysosome pathway. Biochemistry 2021;XXX:XXXX–XXXX.

[51] XieZ, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007;9:1102–9.

[52] OhsumiY. Historical landmarks of autophagy research. Cell Res 2014;24:9–23.

[53] JiCH, KimHY, LeeMJ, et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Commun 2022;13:904.

[54] NomuraD, ZoncuR, WardC, et al. Methods and compounds for targeted antophagy. PCT International Patent WO 2019183600A1, application filed March 22 2019 (2019).

[55] LiZ, WangC, WangZ, et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 2019;575:203–9.

[56] PeiJ, PanX, WangA, et al. Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy. Chem Commun (Camb), 2021;57:13194–7.

[57] FuY, ChenN, WangZ, et al. Degradation of lipid droplets by chimeric autophagy-tethering compounds. Cell Res 2021.

[58] MeliaTJ, LystadAH, SimonsenA. Autophagosome biogenesis: from membrane growth to closure. J Cell Biol 2020;219.

[59] ChangC, JensenLE, HurleyJH. Autophagosome biogenesis comes out of the black box. Nat Cell Biol 2021;23:450–6.

[60] MercerTJ, GubasA, ToozeSA. A molecular perspective of mammalian autophagosome biogenesis. J Biol Chem 2018;293:5386–95.

[61] YuL, ChenY, ToozeSA. Autophagy pathway: cellular and molecular mechanisms. Autophagy 2018;14:207–15.

[62] CarlssonSR, Simonsen A. Membrane dynamics in autophagosome biogenesis. J Cell Sci 2015;128:193–205.

[63] NakatogawaH. Mechanisms governing autophagosome biogenesis. Nat Rev Mol Cell Biol 2020;21:439–58.

[64] DikicI, ElazarZ. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018;19:349–64.

[65] LevineB, Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 2019;176:11–42.

[66] ItakuraE, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 2010;6:764–76.

[67] HurleyJH, YoungLN. Mechanisms of autophagy initiation. Annu Rev Biochem 2017;86:225–44.

[68] NishimuraT, ToozeSA. Emerging roles of ATG proteins and membrane lipids in autophagosome formation. Cell Discov 2020;6:32.

[69] WalkerSA, Ktistakis NT. Autophagosome biogenesis machinery. J Mol Biol 2020;432:2449–61.

[70] LiL, TongM, FuY, et al. Lipids and membrane-associated proteins in autophagy. Protein Cell 2020;12:520–44.

[71] NodaNN. Atg2 and Atg9: intermembrane and interleaflet lipid transporters driving autophagy. Biochim Biophys Acta Mol Cell Biol Lipids 2021;1866:158956.

[72] MizushimaN. The ATG conjugation systems in autophagy. Curr Opin Cell Biol 2020;63:1–10.

[73] JohansenT, LamarkT. Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors. J Mol Biol 2020;432:80–103.

[74] WeschN, KirkinV, RogovVV. Atg8-family proteins—structural features and molecular interactions in autophagy and beyond. Cells 2020;9:2008.

[75] LamarkT, Johansen T. Mechanisms of selective autophagy. Annu Rev Cell Dev Biol 2021;37:143–69.

[76] KirkinV, RogovVVA. Diversity of selective autophagy receptors determines the specificity of the autophagy pathway. Mol Cell 2019;76:268–85.

[77] ManciasJD, WangX, GygiSP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 2014;509:105–9.

[78] MaX, LuC, ChenY, et al. CCT2 is an aggrephagy receptor for clearance of solid protein aggregates. Cell.

[79] StrappazzonF, NazioF, CorradoM, et al. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ 2014;22:419–32.

[80] Di RienzoM, Antonioli M, FuscoC, et al. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Sci Adv 2019;5:eaau8857.

[81] Van HumbeeckC, Cornelissen T, HofkensH, et al. Parkin interacts with Ambra1 to induce mitophagy. J Neurosci 2011;31:10249–61.

[82] OnishiM, YamanoK, SatoM, et al. Molecular mechanisms and physiological functions of mitophagy. EMBO J 2021;40, e104705.

[83] KhaminetsA, Heinrich T, MariM, et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 2015;522:354–8.

[84] ChuCY, JiJ, DagdaRK, et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 2013;15:1197–205.

[85] SentelleRD, SenkalCE, JiangW, et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol 2012;8:831–8.

[86] Hara-KugeS, FujikiY. The peroxin Pex14p is involved in LC3-dependent degradation of mammalian peroxisomes. Exp Cell Res 2008;314:3531–41.

[87] JiangL, Hara-Kuge S, YamashitaS-I, et al. Peroxin Pex14p is the key component for coordinated autophagic degradation of mammalian peroxisomes by direct binding to LC3-II. Genes Cells 2015;20:36–49.

[88] NthigaTM, Shrestha BK, LamarkT, et al. CALCOCO1 is a soluble reticulophagy receptor. Autophagy 2020;16:1729–31.

[89] NthigaTM, Shrestha BK, BruunJA, et al. Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy. J Cell Biol 2021;220.

[90] LuLQ, TangMZ, QiZH, et al. Regulation of the Golgi apparatus via GOLPH3-mediated new selective autophagy. Life Sci 2020;253:117700.

[91] RavenhillBJ, BoyleKB, von MuhlinenN, et al. The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria. Mol Cell 2019;74:320–9 e326.

[92] FilimonenkoM, Isakson P, FinleyKD, et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol Cell 2010;38:265–79.

[93] FoxLM, KimK, JohnsonCW, et al. Huntington’s disease pathogenesis is modified in vivo by Alfy/Wdfy3 and selective macroautophagy. Neuron 2010;105:813–21 e816.

[94] RuiYN, XuZ, PatelB, et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol 2015;17:262–75.

[95] JenaKK, Kolapalli SP, MehtoS, et al. TRIM16 controls turnover of protein aggregates by modulating NRF2, ubiquitin system, and autophagy: implication for tumorigenesis. Mol Cell Oncol 2018;5:e1532251.

[96] ThurstonTL, WandelMP, von MuhlinenN, et al. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 2012;482:414–8.

[97] ChauhanS, KumarS, JainA, et al. TRIMs and galectins globally cooperate and TRIM16 and galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev Cell 2016;39:13–27.

[98] JiCH, KimHY, HeoAJ, et al. The N-degron pathway mediates ER-phagy. Mol Cell 2019;75:1058–72.e1059.

[99] Princely AbuduY, PankivS, MathaiBJ, et al. NIPSNAP1 and NIPSNAP2 act as „eat me” signals for mitophagy. Dev Cell 2019;49:509–25 e512.

[100] JenaKK, MehtoS, KolapalliSP, et al. TRIM16 governs the biogenesis and disposal of stress-induced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer. Autophagy 2019;15:924–6.

[101] MiyakawaK, NishiM, OgawaM, et al. Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins. Nat Commun 2022;13:531.

[102] KoyanoF, OkatsuK, KosakoH, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014;510:162–6.

[103] ChenBH, ChangYJ, LinS, et al. Hsc70/Stub1 promotes the removal of individual oxidatively stressed peroxisomes. Nat Commun 2020;11:5267.

[104] HuettA, HeathRJ, BegunJ, et al. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe 2012;12:778–90.

[105] PapadopoulosC, KravicB, MeyerH. Repair or lysophagy: dealing with damaged lysosomes. J Mol Biol 2020;432:231–9.

[106] ZhenY, Radulovic M, VietriM, et al. Sealing holes in cellular membranes. The EMBO J 2021;40:e106922.

[107] VarshavskyA. N-degron and C-degron pathways of protein degradation. Proc Natl Acad Sci U S A 2019;116:358–66.

[108] Cha-MolstadH, SungKS, HwangJ, et al. Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding. Nat Cell Biol 2015;17:917–29.

[109] Cha-MolstadH, LeeSH, KimJG, et al. Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway. Autophagy 2019;14:359–61.

[110] KimuraT, Mandell M, DereticV. Precision autophagy directed by receptor regulators - emerging examples within the TRIM family. J Cell Sci 2016;129:881–91.

[111] KimuraT, JainA, ChoiSW, et al. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol 2015;210:973–89.

[112] VargasJNS, WangC, BunkerE, et al. Spatiotemporal control of ULK1 activation by NDP52 and TBK1 during selective autophagy. Mol Cell 2019;74:347–62 e346.

[113] ThurstonTL, BoyleKB, AllenM, et al. Recruitment of TBK1 to cytosol- invading Salmonella induces WIPI2-dependent antibacterial autophagy. EMBO J 2016;35:1779–92.

[114] KroemerG, MarinoG, LevineB. Autophagy and the integrated stress response. Mol Cell 2010;40:280–93.

[115] KirkinV. History of the selective autophagy research: how did it begin and where does it stand today? J Mol Biol 2020;432:3–27.

[116] AbdrakhmanovA, Gogvadze V, ZhivotovskyB. To eat or to die: deciphering selective forms of autophagy. Trends Biochem Sci 2020;45:347–64.

[117] ZaffagniniG, Martens, S. Mechanisms of selective autophagy. J Mol Biol 2016;428:1714–24.

[118] EickhorstC, Licheva M, KraftC. Scaffold proteins in bulk and selective autophagy. Prog Mol Biol Transl Sci 2020;172:15–35.

[119] StolzA, ErnstA, DikicI. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 2014;16:495–501.

[120] GaticaD, LahiriV, KlionskyDJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol 2018;20:233–42.

[121] KhaminetsA, BehlC, DikicI. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol 2016;26:6–16.

[122] GrumatiP, DikicI. Ubiquitin signaling and autophagy. J Biol Chem 2018;293:5404–13.

[123] TurcoE, Fracchiolla D, Martens,S. Recruitment and activation of the ULK1/Atg1 kinase complex in selective autophagy. J Mol Biol 2020;432:123–34.

[124] YangQ, ZhaoJ, ChenD, et al. E3 ubiquitin ligases: styles, structures and functions. Mol Biomed 2021;2:23.

[125] YauR, RapeM. The increasing complexity of the ubiquitin code. Nat Cell Biol 2016;18:579–86.

[126] HaakonsenDL, RapeM. Branching out: improved signaling by heterotypic ubiquitin chains. Trends Cell Biol 2019;29:704–16.

[127] OhE, Akopian D, RapeM. Principles of ubiquitin-dependent signaling. Annu Rev Cell Dev Biol 2018;34:137–62.

[128] KwonYT, Ciechanover A. The ubiquitin code in the ubiquitin- proteasome system and autophagy. Trends Biochem Sci 2017;42:873–86.

[129] LamarkT, Johansen T. Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int J Cell Biol 2012;2012:736905.

[130] YaoTP. The role of ubiquitin in autophagy-dependent protein aggregate processing. Genes Cancer 2010;1:779–86.

[131] MatsudaN, SatoS, ShibaK, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010;189:211–21.

[132] KaneLA, Lazarou M, FogelAI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 2014;205:143–53.

[133] PalikarasK, Lionaki E, TavernarakisN. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 2018;20:1013–22.

[134] ZachariM, Gudmundsson SR, LiZ, et al. Selective autophagy of mitochondria on a ubiquitin-endoplasmic-reticulum platform. Dev Cell 2019;50:627–43.e625.

[135] FarréJC, Mahalingam SS, ProiettoM, et al. Peroxisome biogenesis, membrane contact sites, and quality control. EMBO Rep 2019;20.

[136] PolajnarM, DietzMS, HeilemannM, et al. Expanding the host cell ubiquitylation machinery targeting cytosolic Salmonella. EMBO Rep 2017;18:1572–85.

[137] ItoC, SaitoY, NozawaT, et al. Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria. Mol Cell 2013;52:794–804.

[138] YamadaA, Hikichi M, NozawaT, et al. FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan. EMBO Rep 2021;22:e52584.

[139] OttenEG, WernerE, Crespillo-CasadoA, et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 2021;594:111–6.

[140] NoadJ, von der Malsburg A, PatheC, et al. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat Microbiol 2017;2:17063.

[141] FrancoLH, NairVR, ScharnCR, et al. The ubiquitin ligase Smurf1 functions in selective autophagy of Mycobacterium tuberculosis and anti-tuberculous host defense. Cell Host Microbe 2017;21:59–72.

[142] ManzanilloPS, AyresJS, WatsonRO, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 2013;501:512–6.

[143] Cohen-KaplanV, LivnehI, AvniN, et al. p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc Natl Acad Sci U S A 2016;113:E7490–9.

[144] ChoiWH, YunY, ParkS, et al. Aggresomal sequestration and STUB1-mediated ubiquitylation during mammalian proteaphagy of inhibited proteasomes. Proc Natl Acad Sci U S A 2020;117:19190–200.

[145] HouP, YangK, JiaP, et al. A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection. Cell Res 2021;31:62–79.

[146] SimonsenA, Birkeland HC, GilloolyDJ, et al. Alfy, a novel FYVEdomain- containing protein associated with protein granules and autophagic membranes. J Cell Sci 2004;117:4239–51.

[147] LiuX, LiY, WangX, et al. The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy. J Cell Biol 2017;216:1301–20.

[148] YoonMJ, ChoiB, KimEJ, et al. UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy. Nat Commun 2021;12:1955.

[149] JenaKK, Kolapalli SP, MehtoS, et al. TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy. EMBO J 2018;37.

[150] DanieliA, Martens S. p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy. J Cell Sci 2018;131.

[151] SunD, WuR, ZhengJ, et al. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res 2018;28:405–15.

[152] ZaffagniniG, SavovaA, DanieliA, et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J 2018;37.

[153] SunD, WuR, LiP, et al. Phase separation in regulation of aggrephagy. J Mol Biol 2018;432:160–9.

[154] NodaNN, WangZ, ZhangH. Liquid-liquid phase separation in autophagy. J Cell Biol 2020;219.

[155] WurzerB, Zaffagnini G, FeacchiollaD, et al. Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. Elife 2015;4:e08941.

[156] LongJ, Gallagher TR, CaveyJR, et al. Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a novel conformational switch. J Biol Chem 2008;283:5427–40.

[157] NakazawaS, OikawaD, IshiiR, et al. Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis. Nat Commun 2016;7:12547.

[158] LiF, XuD, WangY, et al. Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation. Autophagy 2018;14:66–79.

[159] KomanderD, RapeM. The ubiquitin code. Ann Rev Biochem 2012;81:203–29.

[160] GriceGL, NathanJA. The recognition of ubiquitinated proteins by the proteasome. Cell Mol Life Sci 2016;73:3497–506.

[161] KimI, Lemasters JJ. Mitochondrial degradation by autophagy (mitophagy) in GFP-LC3 transgenic hepatocytes during nutrient deprivation. Am J Physiol-Cell Physiol 2010;300:C308–17.

[162] TwigG, ElorzaA, MolinaAJA, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008;27:433–46.

[163] PapadopoulosC, MeyerH. Detection and clearance of damaged lysosomes by the endo-lysosomal damage response and lysophagy. Curr Biol 2017;27:R1330–41.

[164] HongMH, WengIC, LiFY, et al. Intracellular galectins sense cytosolically exposed glycans as danger and mediate cellular responses. J Biomed Sci 2021;28:16.

[165] NguyenKM, BusinoL. The biology of F-box proteins: the SCF family of E3 ubiquitin ligases. Adv Exp Med Biol 2020;1217:111–22.

[166] YoshidaY, Mizushima T, TanakaK. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Front Physiol 2019;10:104.

[167] YoshidaY, YasudaS, FujidaT, et al. Ubiquitination of exposed glycoproteins by SCF(FBXO27) directs damaged lysosomes for autophagy. Proc Natl Acad Sci U S A 2017;114:8574–9.

[168] LiuEA, Schultz ML, MochidaC, et al. Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain. JCI Insight 2020;5.

[169] JohannesL, JacobR, LefflerH. Galectins at a glance. J Cell Sci 2018;131.

[170] ChengYL, WuYW, KuoCF, et al. Galectin-3 inhibits galectin-8/parkin- mediated ubiquitination of group A streptococcus. mBio 2017;8.

[171] BellSL, LopezKL, CoxJS, et al. Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to control Mycobacterium tuberculosis infection in macrophages. mBio, 2021;e0187120.

[172] FalconB, NoadJ, McMahonH, et al. Galectin-8-mediated selective autophagy protects against seeded tau aggregation. J Biol Chem 2018;293:2438–51.

[173] YooYD, MunSR, JiC, et al. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. Proc Natl Acad Sci U S A 2018;115:E2716–24.

[174] Cha-MolstadH, YuJE, FengZ, et al. p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat Commun 2017;8:102.

[175] ChinoH, Mizushima N. ER-phagy: quality control and turnover of endoplasmic reticulum. Trends Cell Biol 2020;30:384–98.

[176] SmithMD, HarleyME, KempAJ, et al. CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev Cell 2018;44:217–32.e211.

[177] ZhouZ, LiuJ, FuT, et al. Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation. Nat Commun 2021;12:1570.

[178] KostenkoEV, Olabisi OO, SahayS, et al. Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs. Mol Cell Biol 2006;26:8964–75.

[179] BhaskaraRM, Grumati P, Garcia-PardoJ, et al. Curvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy. Nat Commun 2019;10:2370.

[180] ForresterA, De Leonibus C, GrumatiP, et al. A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex. EMBO J 2019;38:e99847.

[181] ZhaoJ, LiZ, LiJ. The crystal structure of the FAM134B-GABARAP complex provides mechanistic insights into the selective binding of FAM134 to the GABARAP subfamily. FEBS Open Bio, 2021.

[182] GrumatiP, Morozzi G, HölperS, et al. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. Elife 2017;6:e25555.

[183] ChenYJ, KnuppJ, ArunagiriA, et al. PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones. Nat Commun 2021;12:5991.

[184] AnH, Ordureau A, PauloJA, et al. TEX264 is an endoplasmic reticulum- resident ATG8-interacting protein critical for ER remodeling during nutrient stress. Mol Cell 2019;74:891–908 e810.

[185] ChinoH, HattaT, NatsumeT, et al. Intrinsically disordered protein TEX264 mediates ER-phagy. Mol Cell 2019;74:909–21 e906.

[186] FumagalliF, NoackJ, BergmannTJ, et al. Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol 2016;18:1173–84.

[187] ChenQ, XiaoY, ChaiP, et al. ATL3 is a tubular ER-phagy receptor for GABARAP-mediated selective autophagy. Curr Biol 2019;29:846–55 e846.

[188] BhujabalZ, Birgisdottir ÅB, SjøttemE, et al. FKBP8 recruits LC3A to mediate Parkin-independent mitophagy. EMBO Rep 2017;18:947–61.

[189] LiM, JiaJ, ZhangX, et al. Selective binding of mitophagy receptor protein Bcl-rambo to LC3/GABARAP family proteins. Biochem Biophys Res Commun 2020;530:292–300.

[190] MurakawaT, Yamaguchi O, HashimotoA, et al. Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun 2015;6:7527.

[191] MurakawaT, Okamoto K, OmiyaS, et al. A mammalian mitophagy receptor, Bcl2-L-13, recruits the ULK1 complex to induce mitophagy. Cell Rep 2019;26:338–45.e336.

[192] LiuL, FengD, ChenG, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 2012;14:177–85.

[193] WeiY, ChiangWC, SumpterR, et al. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 2017;168:224–38. e210.

[194] ChuCT. Mechanisms of selective autophagy and mitophagy: implications for neurodegenerative diseases. Neurobiol Dis 2019;122:23–34.

[195] FritschLE, MooreME, SarrafSA, et al. Ubiquitin and receptor-dependent mitophagy pathways and their implication in neurodegeneration. J Mol Biol 2020;432:2510–24.

[196] GryzikM, Srivastava A, LonghiG, et al. Expression and characterization of the ferritin binding domain of Nuclear Receptor Coactivator-4 (NCOA4). Biochim Biophys Acta Gen Subj 2017;1861:2710–6.

[197] OhshimaT, Yamamoto H, SakamakiY, et al. NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and endosomal microferritinophagy. bioRxiv 2022.2001.2031.478434, 2022, preprint: not peer reviewed.

[198] JiangS, HellerB, TagliabracciVS, et al. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J Biol Chem 2010;285:34960–71.

[199] JiangS, WellsCD, Roach,PJ. Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun 2011;413:420–5.

[200] WyantGA, Abu-Remaileh M, FrenkelEM, et al. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 2018;360:751–8.

[201] MandellMA, JainA, Arko-MensahJ, et al. TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev Cell 2014;30:394–409.

[202] IchimuraY, WaguriS, SouYS, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 2013;51:618–31.

[203] KatsuragiY, Ichimura Y, KomatsuM. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J 2015;282:4672–8.

[204] DeosaranE, LarsenKB, HuaR, et al. NBR1 acts as an autophagy receptor for peroxisomes. J Cell Sci 2013;126:939–52.

[205] Zientara-RytterK, Subramani S. Autophagic degradation of peroxisomes in mammals. Biochem Soc Trans 2016;44:431–40.

[206] Minowa-NozawaA, NozawaT, Okamoto-FurutaK, et al. Rab35 GTPase recruits NDP52 to autophagy targets. Embo J 2017;36:2790–807.

[207] FuruyaN, KakutaS, SumiyoshiK, et al. NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy. EMBO Rep 2018;19.

[208] KoracJ, Schaeffer V, KovacevicI, et al. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J Cell Sci 2013;126:580–92.

[209] LinCY, NozawaT, Minowa-NozawaA, et al. Autophagy receptor tollip facilitates bacterial autophagy by recruiting galectin-7 in response to group A streptococcus infection. Front Cell Infect Microbiol 2020;10,583137.

[210] ZachariM, GanleyIG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem 2017;61:585–96.

[211] KumarS, JavedR, MuddM, et al. Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes. Cell 2021;184:5950–69.e5922.

[212] TurcoE, et al. FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Mol Cell 2019;74,:330–46 e311.

[213] TurcoE, SavovaA, GereF, et al. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat Commun 2021;12:5212.

[214] WuW, TianW, HuZ, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 2014;15:566–75.

[215] OhnstadAE, Delgado JM, NorthBJ, et al. Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. EMBO J 2020;39:e104948.

[216] KtistakisNT. The dynamics of mitochondrial autophagy at the initiation stage. Biochem Soc Trans 2021;49:2199–210.

[217] Dalle PezzeP, Karanasios E, KandiaV, et al. ATG13 dynamics in nonselective autophagy and mitophagy: insights from live imaging studies and mathematical modeling. Autophagy 2021;17:1131–41.

[218] ShiX, ChangC, YokomAL, et al. The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. Elife 2020;9.

[219] HeoJM, Ordureau A, PauloJA, et al. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell 2015;60:7–20.

[220] SchlütermannD, Berleth N, DeitersenJ, et al. FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates. Sci Rep 2021;11:13863.

[221] RichterB, SliterDA, HerhausL, et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 2016;113:4039–44.

[222] MaX, Helgason E, PhungQT, et al. Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation. Proc Natl Acad Sci U S A 2012;109:9378–83.

[223] LarabiA, DevosJM, NgSL, et al. Crystal structure and mechanism of activation of TANK-binding kinase 1. Cell Rep 2013;3:734–46.

[224] HelgasonE, PhungQT, DueberEC. Recent insights into the complexity of Tank-binding kinase 1 signaling networks: the emerging role of cellular localization in the activation and substrate specificity of TBK1. FEBS Lett 2013;587:1230–37.

[225] MatsumotoG, Shimogori T, HattoriN, et al. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum Mol Genet 2015;24:4429–42.

[226] MatsumotoG, WadaK, OkunoM, et al. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 2011;44:279–89.

[227] MooreAS, Holzbaur EL. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc Natl Acad Sci U S A 2016;113:E3349–58.

[228] HatakeyamaS. TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci 2017;42:297–311.

[229] Di RienzoM, Romagnoli A, AntonioliM, et al. TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses. Cell Death Differ 2020;27:887–902.

[230] YamanoK, Kikuchi R, KojimaW, et al. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J Cell Biol 2020;219.

[231] LiX, HanH, ZhouMT, et al. Proteomic analysis of the human tankyrase protein interaction network reveals its role in pexophagy. Cell Rep 2017;20:737–49.

[232] FracchiollaD, Sawa-Makarska J, ZensB, et al. Mechanism of cargo- directed Atg8 conjugation during selective autophagy. Elife 2016;5.

[233] MartensS, Fracchiolla D. Activation and targeting of ATG8 protein lipidation. Cell Discov 2020;6:23.

[234] ChangC, YoungLN, MorrisKL, et al. Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy. Sci Adv 2021;7.

[235] BansalM, Maharir SC, SailasreeSP, et al. Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein. J Biol Chem 2018;293:132–47.

[236] FujitaN, ItohT, OmoriH, et al. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 2008;19:2092–100.

[237] MarshallRS, HuaZ, MaliS, et al. ATG8-binding UIM proteins define a new class of autophagy adaptors and receptors. Cell 2019;177:766–81.e724.

[238] HartmannM, HuberJ, KramerJS, et al. Demonstrating ligandability of the LC3A and LC3B adapter interface. J Med Chem 2021;64:3720–46.

[239] SteffekM, Helgason E, PopovychN, et al. A multifaceted hit-finding approach reveals novel LC3 family ligands. Biochemistry 2022.

[240] WangZ, ZhangH. Phase separation, transition, and autophagic degradation of proteins in development and pathogenesis. Trends Cell Biol 2019;29:417–27.

[241] YamasakiA, AlamJM, NoshiroD, et al. Liquidity is a critical determinant for selective autophagy of protein condensates. Mol Cell 2020;77:1163–75 e1169.

[242] PengSZ, ChenXH, ChenSJ, et al. Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates. Nat Commun 2021;12:5989.

[243] YangY, WillisTL, ButtonRW, et al. Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response. Nat Commun 2019;10:3759.

[244] Agudo-CanalejoJ, Schultz SW, ChinoH, et al. Wetting regulates autophagy of phase-separated compartments and the cytosol. Nature 2021;591:142–46.

[245] TanakaA, Cleland MM, XuS, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 2010;191:1367–80.

[246] Di RitaA, Peschiaroli A, D’AcunzoP, et al. HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nat Commun 2018;9:3755.

[247] FuM, St-Pierre P, ShankarJ, et al. Regulation of mitophagy by the Gp78 E3 ubiquitin ligase. Mol Biol Cell 2013;24:1153–62.

[248] TakahashiD, Arimoto, H. Targeting selective autophagy by AUTAC degraders. Autophagy 2020;16:765–6.

[249] RichardTJC, HerzogLK, VornbergerJ, et al. K63-linked ubiquitylation induces global sequestration of mitochondria. Sci Rep 2020;10:22334.

[250] MabeS, Nagamune T, KawaharaM. Detecting protein-protein interactions based on kinase-mediated growth induction of mammalian cells. Sci Rep 2014;4:6127.

[251] StantonBZ, ChoryEJ, CrabtreeGR. Chemically induced proximity in biology and medicine. Science 2018;359:eaao5902.

[252] NarendraD, KaneLA, HauserDN, et al. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 2010;6:1090–106.

[253] LazarouM, JinSM, KaneLA, et al. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell 2012;22:320–33.

[254] D’AcunzoP, Strappazzon F, CaruanaI, et al. Reversible induction of mitophagy by an optogenetic bimodular system. Nat Commun 2019;10, 1533.

[255] LoosF, XieW, SicaV, et al. Artificial tethering of LC3 or p62 to organelles is not sufficient to trigger autophagy. Cell Death Dis 2019;10:771.

[256] TatsumiT, Takayama K, IshiiS, et al. Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse. Development 2018;145.

[257] FanXY, GuoL, ChenLN, et al. Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy. Nat Biomed Eng 2022;6:339–50.

[258] MinamiY, Hoshino A, HiguchiY, et al. Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis. bioRxiv 2022.2002.2022.481456, 2022, preprint: not peer reviewed.

[259] Cha-MolstadH, YuJE, LeeSH, et al. Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP. Autophagy 2016;12:426–8.

[260] GarnerTP, LongJ, LayfieldR, et al. Impact of p62/SQSTM1 UBA domain mutations linked to paget’s disease of bone on ubiquitin recognition. Biochemistry 2011;50:4665–74.

[261] TeyssouE, TakedaT, LebonV, et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol 2013;125:511–22.

[262] DjajadikertaA, KeshriS, PavelM, et al. Autophagy induction as a therapeutic strategy for neurodegenerative diseases. J Mol Biol 2020;432:2799–821.

[263] SureshSN, Chakravorty A, GiridharanM, et al. Pharmacological tools to modulate autophagy in neurodegenerative diseases. J Mol Biol 2020;432:2822–42.

[264] ShimizuY, Yonezawa T, SakamotoJ, et al. Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein–protein interaction-oriented library and machine learning. Sci Rep 2021;11:7420.

[265] CianfanelliV, De ZioD, Di BartolomeoS, et al. Ambra1 at a glance. J Cell Sci 2015;128:2003–8.

[266] LiuP, WangY, ZhouX-M. Reconstitution of adiposome and artificial lipid droplets. FASEB J 2015;29:LB171.

[267] HuangR, XuY, WanW, et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell 2015;57:456–66.

[268] XuC, WangL, FozouniP, et al. SIRT1 is downregulated by autophagy in senescence and ageing. Nat Cell Biol 2015;22:1170–9.

[269] DouZ, XuC, DonahueG, et al. Autophagy mediates degradation of nuclear lamina. Nature 2015;527:105–9.

[270] ReggioriF, Monastyrska I, VerheijeMH, et al. Coronaviruses Hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 2010;7:500–8.

[271] LeidalAM, HuangHH, MarshT, et al. The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles. Nat Cell Biol 2020;22:187–99.

[272] ZhangH, AnP, FeiY, et al. Modeling the degradation effects of autophagosome tethering compounds. Neurosci Bull 2021;37:255–60.

[273] HyslopLA, Blakeley P, CravenL, et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 2016;534:383–6.

[274] KangE, WuJ, GutierrezNM, et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature 2016;540:270–5.

[275] GreenfieldA, BraudeP, FlinterF, et al. Assisted reproductive technologies to prevent human mitochondrial disease transmission. Nat Biotechnol 2017;35:1059–68.

[276] Coll-MartínezB, Delgado A, CrosasB. The potential of proteolytic chimeras as pharmacological tools and therapeutic agents. Molecules 2020;25.

[277] DongG, DingY, HeS, et al. Molecular glues for targeted protein degradation: from serendipity to rational discovery. J Med Chem 2021;64:10606–20.

[278] GeigerTM, Schäfer SC, DreizlerJK, et al. Clues to molecular glues. Curr Res Chem Biol 2022;2:100018.

[279] SchreiberSL. The rise of molecular glues. Cell 2021;184:3–9.

[280] Mayor-RuizC, BauerS, BrandM, et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat Chem Biol 2021;16:1199–207.

[281] IshidaT, CiulliA. E3 ligase ligands for PROTACs: how they were found and how to discover new ones. SLAS Discov 2021;26:484–502.

[282] FisherSL, Phillips AJ. Targeted protein degradation and the enzymology of degraders. Curr Opin Chem Biol 2018;44:47–55.

[283] RambacherKM, Calabrese MF, YamaguchiM. Perspectives on the development of first-in-class protein degraders. Future Med Chem 2021;13:1203–26.

[284] CasementR, BondA, CraigonC, et al. Mechanistic and structural features of PROTAC ternary complexes. Methods Mol Biol 2021;2365:79–113.

[285] BriceljA, Steinebach C, KuchtaR, et al. E3 ligase ligands in successful PROTACs: an overview of syntheses and linker attachment points. Front Chem 2021;9:707317.

[286] RichingKM, MahanS, CoronaCR, et al. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chem Biol 2018;13:2758–70.

[287] NabetB, Roberts JM, BuckleyDL, et al. The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol 2018;14:431–41.

[288] NabetB, Ferguson FM, SeongBKA, et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat Commun 2020;11:4687.

[289] BuckleyDL, RainaK, DarricarrereN, et al. HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins. ACS Chem Biol 2015;10:1831–7.

[290] MenziesFM, Fleming A, RubinszteinDC. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 2015;16:345–57.

[291] RenH, WangG. Autophagy and lysosome storage disorders. Adv Exp Med Biol 2020;1207:87–102.

[292] LiebermanAP, Puertollano R, RabenN, et al. Autophagy in lysosomal storage disorders. Autophagy 2012;8:719–30.

[293] BanerjeeC, MehraD, SongD, et al. ULK1 forms distinct oligomeric states and nanoscopic morphologies during autophagy initiation. bioRxiv 2020.

[294] SternickiLM, Nonomiya J, LiuM, et al. Native mass spectrometry for the study of PROTAC GNE-987-containing ternary complexes. ChemMedChem 2021;16:2206–10.

[295] MathieuC, PappuRV, TaylorJP. Beyond aggregation: pathological phase transitions in neurodegenerative disease. Science 2020;370:56–60.

[296] RayS, SinghN, KumarR, et al. α-Synuclein aggregation nucleates through liquid–liquid phase separation. Nat Chem 2020;12:705–16.

[297] ZbindenA, Pérez-Berlanga M, De Rossi,P, et al. Phase separation and neurodegenerative diseases: a disturbance in the force. Dev Cell 2020;55:45–68.

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