Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

  • Ji, Chang Hoon (Protein Metabolism Medical Research Center and Department of Biomedical Sciences, Seoul National University) ;
  • Kwon, Yong Tae (Protein Metabolism Medical Research Center and Department of Biomedical Sciences, Seoul National University)
  • Received : 2017.07.06
  • Accepted : 2017.07.12
  • Published : 2017.07.31
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Abstract

Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

Keywords

References

  1. Akutsu, M., Dikic, I., and Bremm, A. (2016). Ubiquitin chain diversity at a glance. J. Cell Sci. 129, 875-880. https://doi.org/10.1242/jcs.183954
  2. B'Chir, W., Maurin, A.C., Carraro, V., Averous, J., Jousse, C., Muranishi, Y., Parry, L., Stepien, G., Fafournoux, P., and Bruhat, A. (2013). The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683-7699. https://doi.org/10.1093/nar/gkt563
  3. Bachmair, A., Finley, D., and Varshavsky, A. (1986). In vivo half-life of a protein is a function of its amino-terminal residue. Science 234, 179-186. https://doi.org/10.1126/science.3018930
  4. Bao, X., Ren, T., Huang, Y., Ren, C., Yang, K., Zhang, H., and Guo, W. (2017). Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma. Int. J. Oncol. 50, 477-486. https://doi.org/10.3892/ijo.2016.3806
  5. Bates, G.P., Dorsey, R., Gusella, J.F., Hayden, M.R., Kay, C., Leavitt, B.R., Nance, M., Ross, C.A., Scahill, R.I., Wetzel, R., et al. (2015). Huntington disease. Nat. Rev. Dis. Primers 1, 15005.
  6. Bayraktar, O., Oral, O., Kocaturk, N.M., Akkoc, Y., Eberhart, K., Kosar, A., and Gozuacik, D. (2016). IBMPFD disease-causing mutant VCP/p97 proteins are targets of autophagic-lysosomal degradation. PLoS One 11, e0164864. https://doi.org/10.1371/journal.pone.0164864
  7. Blessing, N.A., Brockman, A.L., and Chadee, D.N. (2014). The E3 ligase CHIP mediates ubiquitination and degradation of mixed-lineage kinase 3. Mol. Cell. Biol. 34, 3132-3143. https://doi.org/10.1128/MCB.00296-14
  8. Braten, O., Livneh, I., Ziv, T., Admon, A., Kehat, I., Caspi, L.H., Gonen, H., Bercovich, B., Godzik, A., Jahandideh, S., et al. (2016). Numerous proteins with unique characteristics are degraded by the 26S proteasome following monoubiquitination. Proc. Natl. Acad. Sci. USA 113, E4639-4647. https://doi.org/10.1073/pnas.1608644113
  9. Brown, N.G., VanderLinden, R., Watson, E.R., Weissmann, F., Ordureau, A., Wu, K.P., Zhang, W., Yu, S., Mercredi, P.Y., Harrison, J.S., et al. (2016). Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C. Cell 165, 1440-1453. https://doi.org/10.1016/j.cell.2016.05.037
  10. Budenholzer, L., Cheng, C.L., Li, Y., and Hochstrasser, M. (2017). Proteasome structure and Assembly. J. Mol. Biol. pii: S0022-2836(17)30270-X.
  11. Cha-Molstad, H., Sung, K.S., Hwang, J., Kim, K.A., Yu, J.E., Yoo, Y.D., Jang, J.M., Han, D.H., Molstad, M., Kim, J.G., et al. (2015). Aminoterminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding. Nat. Cell Biol. 17, 917-929. https://doi.org/10.1038/ncb3177
  12. Cha-Molstad, H., Yu, J.E., Lee, S.H., Kim, J.G., Sung, K.S., Hwang, J., Yoo, Y.D., Lee, Y.J., Kim, S.T., Lee, D.H., et al. (2016). Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP. Autophagy 12, 426-428. https://doi.org/10.1080/15548627.2015.1126047
  13. Cha-Molstad, H., Yu, J.E., Lee, S.H., Feng, Z., Lee, S.H., Kim, J.G., Yang, P., Han, B., Sung, K.W., Yoo, Y.D., et al. (in press). p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway, which modulates autophagosome biogenesis. Nat. Commun.
  14. Ciechanover, A. (2015). The unravelling of the ubiquitin system. Na. Rev. Mol. Cell Biol. 16, 322-324. https://doi.org/10.1038/nrm3982
  15. Ciechanover, A., and Kwon, Y.T. (2015). Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp. Mol. Med. 47, e147. https://doi.org/10.1038/emm.2014.117
  16. Ciechanover, A., and Kwon, Y.T. (2017). Protein Quality Control by Molecular Chaperones in Neurodegeneration. Front. Neurosci. 11, 185.
  17. Cohen-Kaplan, V., Ciechanover, A., and Livneh, I. (2017). Stressinduced polyubiquitination of proteasomal ubiquitin receptors targets the proteolytic complex for autophagic degradation. Autophagy 13, 759-760. https://doi.org/10.1080/15548627.2016.1278327
  18. Collins, G.A., and Goldberg, A.L. (2017). The logic of the 26S proteasome. Cell 169, 792-806. https://doi.org/10.1016/j.cell.2017.04.023
  19. Cristofani, R., Crippa, V., Rusmini, P., Cicardi, M.E., Meroni, M., Licata, N.V., Sala, G., Giorgetti, E., Grunseich, C., Galbiati, M., et al. (2017). Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases. Autophagy doi: 10.1080/15548627.2017.1308985. [Epub ahead of print].
  20. Crosas, B., Hanna, J., Kirkpatrick, D.S., Zhang, D.P., Tone, Y., Hathaway, N.A., Buecker, C., Leggett, D.S., Schmidt, M., King, R.W., et al. (2006). Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127, 1401-1413. https://doi.org/10.1016/j.cell.2006.09.051
  21. Cunningham, C.N., Baughman, J.M., Phu, L., Tea, J.S., Yu, C., Coons, M., Kirkpatrick, D.S., Bingol, B., and Corn, J.E. (2015). USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nat. Cell Biol. 17, 160-169. https://doi.org/10.1038/ncb3097
  22. Deegan, S., Saveljeva, S., Gorman, A.M., and Samali, A. (2013). Stressinduced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress. Cell. Mol. Life Sci. 70, 2425-2441. https://doi.org/10.1007/s00018-012-1173-4
  23. Deng, Z., Purtell, K., Lachance, V., Wold, M.S., Chen, S., and Yue, Z. (2017). Autophagy receptors and neurodegenerative diseases. Trends Cell Biol. 27, 491-504. https://doi.org/10.1016/j.tcb.2017.01.001
  24. Dwane, L., Gallagher, W.M., Ni Chonghaile, T., and O'Connor, D.P. (2017). The emerging role of non-traditional ubiquitination in oncogenic pathways. J. Biol. Chem. 292, 3543-3551. https://doi.org/10.1074/jbc.R116.755694
  25. Feng, L., Zhang, J., Zhu, N., Ding, Q., Zhang, X., Yu, J., Qiang, W., Zhang, Z., Ma, Y., Huang, D., et al. (2017). Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/alpha-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy. Autophagy 13, 686-702. https://doi.org/10.1080/15548627.2017.1280207
  26. Ferreira, J.V., Soares, A.R., Ramalho, J.S., Pereira, P., and Girao, H. (2015). K63 linked ubiquitin chain formation is a signal for HIF1A degradation by chaperone-mediated autophagy. Sci. Rep. 5, 10210. https://doi.org/10.1038/srep10210
  27. French, M.E., Klosowiak, J.L., Aslanian, A., Reed, S.I., Yates, J.R., 3rd and Hunter, T. (2017). Mechanism of ubiquitin chain synthesis employed by a HECT domain ubiquitin ligase. J. Biol. Chem. 292, 10398-10413. https://doi.org/10.1074/jbc.M117.789479
  28. Gade, P., Ramachandran, G., Maachani, U.B., Rizzo, M.A., Okada, T., Prywes, R., Cross, A.S., Mori, K., and Kalvakolanu, D.V. (2012). An IFNgamma-stimulated ATF6-C/EBP-beta-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc. Natl. Acad. Sci. USA 109, 10316-10321. https://doi.org/10.1073/pnas.1119273109
  29. Greene, C.M., Marciniak, S.J., Teckman, J., Ferrarotti, I., Brantly, M.L., Lomas, D.A., Stoller, J.K., and McElvaney, N.G. (2016). alpha1-Antitrypsin deficiency. Nat. Rev. Dis. Primers 2, 16051. https://doi.org/10.1038/nrdp.2016.51
  30. Grice, G.L., and Nathan, J.A. (2016). The recognition of ubiquitinated proteins by the proteasome. Cell. Mol. Life Sci. 73, 3497-3506. https://doi.org/10.1007/s00018-016-2255-5
  31. Gu, D., Wang, S., Kuiatse, I., Wang, H., He, J., Dai, Y., Jones, R.J., Bjorklund, C.C., Yang, J., Grant, S., et al. (2014). Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737. PLoS One 9, e103015. https://doi.org/10.1371/journal.pone.0103015
  32. Harada, M., Hanada, S., Toivola, D.M., Ghori, N., and Omary, M.B. (2008). Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. Hepatology 47, 2026-2035. https://doi.org/10.1002/hep.22294
  33. Hetz, C., Chevet, E., and Oakes, S.A. (2015). Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829-838. https://doi.org/10.1038/ncb3184
  34. Hidvegi, T., Ewing, M., Hale, P., Dippold, C., Beckett, C., Kemp, C., Maurice, N., Mukherjee, A., Goldbach, C., Watkins, S., et al. (2010). An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229-232. https://doi.org/10.1126/science.1190354
  35. Hipp, M.S., Patel, C.N., Bersuker, K., Riley, B.E., Kaiser, S.E., Shaler, T.A., Brandeis, M., and Kopito, R.R. (2012). Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease. J. Cell Biol. 196, 573-587. https://doi.org/10.1083/jcb.201110093
  36. Hyttinen, J.M., Amadio, M., Viiri, J., Pascale, A., Salminen, A., and Kaarniranta, K. (2014). Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases. Ageing Res. Rev. 18, 16-28. https://doi.org/10.1016/j.arr.2014.07.002
  37. Jing, K., Song, K.S., Shin, S., Kim, N., Jeong, S., Oh, H.R., Park, J.H., Seo, K.S., Heo, J.Y., Han, J., et al. (2011). Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy 7, 1348-1358. https://doi.org/10.4161/auto.7.11.16658
  38. Kim, H.C., and Huibregtse, J.M. (2009). Polyubiquitination by HECT E3s and the determinants of chain type specificity. Mol. Cell. Biol. 29, 3307-3318. https://doi.org/10.1128/MCB.00240-09
  39. Kim, W., Bennett, E.J., Huttlin, E.L., Guo, A., Li, J., Possemato, A., Sowa, M.E., Rad, R., Rush, J., Comb, M.J., et al. (2011). Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44, 325-340. https://doi.org/10.1016/j.molcel.2011.08.025
  40. Kirkin, V., Lamark, T., Sou, Y.S., Bjorkoy, G., Nunn, J.L., Bruun, J.A., Shvets, E., McEwan, D.G., Clausen, T.H., Wild, P., et al. (2009). A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505-516. https://doi.org/10.1016/j.molcel.2009.01.020
  41. Korolchuk, V.I., Mansilla, A., Menzies, F.M., and Rubinsztein, D.C. (2009). Autophagy inhibition compromises degradation of ubiquitinproteasome pathway substrates. Mol. Cell 33, 517-527. https://doi.org/10.1016/j.molcel.2009.01.021
  42. Kwon, Y.T., Reiss, Y., Fried, V.A., Hershko, A., Yoon, J.K., Gonda, D.K., Sangan, P., Copeland, N.G., Jenkins, N.A., and Varshavsky, A. (1998). The mouse and human genes encoding the recognition component of the N-end rule pathway. Proc. Natl. Acad. Sci. USA 95, 7898-7903. https://doi.org/10.1073/pnas.95.14.7898
  43. Kwon, Y.T., Kashina, A.S., and Varshavsky, A. (1999). Alternative splicing results in differential expression, activity, and localization of the two forms of arginyl-tRNA-protein transferase, a component of the Nend rule pathway. Mol. Cell. Biol. 19, 182-193. https://doi.org/10.1128/MCB.19.1.182
  44. Kwon, Y.T., Kashina, A.S., Davydov, I.V., Hu, R.G., An, J.Y., Seo, J.W., Du, F., and Varshavsky, A. (2002). An essential role of N-terminal arginylation in cardiovascular development. Science 297, 96-99. https://doi.org/10.1126/science.1069531
  45. Lagunas-Martinez, A., Garcia-Villa, E., Arellano-Gaytan, M., Contreras-Ochoa, C.O., Dimas-Gonzalez, J., Lopez-Arellano, M.E., Madrid-Marina, V., and Gariglio, P. (2017). MG132 plus apoptosis antigen-1 (APO-1). antibody cooperate to restore p53 activity inducing autophagy and p53-dependent apoptosis in HPV16 E6-expressing keratinocytes. Apoptosis 22, 27-40. https://doi.org/10.1007/s10495-016-1299-1
  46. Liu, W., Shang, Y., and Li, W. (2014). gp78 elongates of polyubiquitin chains from the distal end through the cooperation of its G2BR and CUE domains. Sci. Rep. 4, 7138.
  47. Liu, C., Liu, W., Ye, Y., and Li, W. (2017). Ufd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains. Nat. Commun. 8, 14274. https://doi.org/10.1038/ncomms14274
  48. Locke, M., Toth, J.I., and Petroski, M.D. (2014). Lys11- and Lys48-linked ubiquitin chains interact with p97 during endoplasmic-reticulumassociated degradation. Biochem. J. 459, 205-216. https://doi.org/10.1042/BJ20120662
  49. Lu, D., Girard, J.R., Li, W., Mizrak, A., and Morgan, D.O. (2015a). Quantitative framework for ordered degradation of APC/C substrates. BMC Biol. 13, 96. https://doi.org/10.1186/s12915-015-0205-6
  50. Lu, Y., Lee, B.H., King, R.W., Finley, D., and Kirschner, M.W. (2015b). Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 348, 1250834. https://doi.org/10.1126/science.1250834
  51. Marshall, R.S., Li, F., Gemperline, D.C., Book, A.J., and Vierstra, R.D. (2015). Autophagic Degradation of the 26S proteasome is mediated by the dual ATG8/ubiquitin receptor RPN10 in arabidopsis. Mol. Cell 58, 1053-1066. https://doi.org/10.1016/j.molcel.2015.04.023
  52. Marshall, R.S., McLoughlin, F., and Vierstra, R.D. (2016). Autophagic turnover of inactive 26S proteasomes in yeast is directed by the ubiquitin receptor Cue5 and the Hsp42 chaperone. Cell Rep. 16, 1717-1732. https://doi.org/10.1016/j.celrep.2016.07.015
  53. Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M., and Nukina, N. (2011). Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell 44, 279-289. https://doi.org/10.1016/j.molcel.2011.07.039
  54. McKeon, J.E., Sha, D., Li, L., and Chin, L.S. (2015). Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system. Cell. Mol. Life Sci. 72, 1811-1824. https://doi.org/10.1007/s00018-014-1781-2
  55. Minoia, M., Boncoraglio, A., Vinet, J., Morelli, F.F., Brunsting, J.F., Poletti, A., Krom, S., Reits, E., Kampinga, H.H., and Carra, S. (2014). BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta: implications for a proteasome-to-autophagy switch. Autophagy 10, 1603-1621. https://doi.org/10.4161/auto.29409
  56. Morris, J.R., and Garvin, A.J. (2017). SUMO in the DNA doublestranded break response: similarities, differences, and cooperation with ubiquitin. J. Mol. Biol. pii: S0022-2836(17)30227-9.
  57. Mrschtik, M., O'Prey, J., Lao, L.Y., Long, J.S., Beaumatin, F., Strachan, D., O'Prey, M., Skommer, J., and Ryan, K.M. (2015). DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. Cell Death Differ. 22, 1714-1726. https://doi.org/10.1038/cdd.2015.26
  58. Munch, D., Rodriguez, E., Bressendorff, S., Park, O.K., Hofius, D., and Petersen, M. (2014). Autophagy deficiency leads to accumulation of ubiquitinated proteins, ER stress, and cell death in Arabidopsis. Autophagy 10, 1579-1587. https://doi.org/10.4161/auto.29406
  59. Ohtake, F., and Tsuchiya, H. (2017). The emerging complexity of ubiquitin architecture. J. Biochem. 161, 125-133.
  60. Pan, T., Kondo, S., Zhu, W., Xie, W., Jankovic, J., and Le, W. (2008). Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16-25. https://doi.org/10.1016/j.nbd.2008.06.003
  61. Pandey, U.B., Nie, Z., Batlevi, Y., McCray, B.A., Ritson, G.P., Nedelsky, N.B., Schwartz, S.L., DiProspero, N.A., Knight, M.A., Schuldiner, O., et al. (2007). HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859-863.
  62. Park, H.S., Jun do, Y., Han, C.R., Woo, H.J., and Kim, Y.H. (2011). Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells. Biochem. Pharmacol.82, 1110-1125. https://doi.org/10.1016/j.bcp.2011.07.085
  63. Poewe, W., Seppi, K., Tanner, C.M., Halliday, G.M., Brundin, P., Volkmann, J., Schrag, A.E., and Lang, A.E. (2017). Parkinson disease. Nat. Rev. Dis. Primers 3, 17013. https://doi.org/10.1038/nrdp.2017.13
  64. Qin, Y., Zhou, M.T., Hu, M.M., Hu, Y.H., Zhang, J., Guo, L., Zhong, B., and Shu, H.B. (2014). RNF26 temporally regulates virus-triggered type I interferon induction by two distinct mechanisms. PLoS Pathogens 10, e1004358. https://doi.org/10.1371/journal.ppat.1004358
  65. Richly, H., Rape, M., Braun, S., Rumpf, S., Hoege, C., and Jentsch, S. (2005). A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73-84. https://doi.org/10.1016/j.cell.2004.11.013
  66. Riley, B.E., Kaiser, S.E., Shaler, T.A., Ng, A.C., Hara, T., Hipp, M.S., Lage, K., Xavier, R.J., Ryu, K.Y., Taguchi, K., et al. (2010). Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J. Cell Biol. 191, 537-552. https://doi.org/10.1083/jcb.201005012
  67. Saeki, Y., Kudo, T., Sone, T., Kikuchi, Y., Yokosawa, H., Toh-e, A., and Tanaka, K. (2009). Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J. 28, 359-371. https://doi.org/10.1038/emboj.2008.305
  68. Scott, D., Oldham, N.J., Strachan, J., Searle, M.S., and Layfield, R. (2015). Ubiquitin-binding domains: mechanisms of ubiquitin recognition and use as tools to investigate ubiquitin-modified proteomes. Proteomics 15, 844-861. https://doi.org/10.1002/pmic.201400341
  69. Seeler, J.S., and Dejean, A. (2017). SUMO and the robustness of cancer. Nat. Rev. Cancer 17, 184-197. https://doi.org/10.1038/nrc.2016.143
  70. Sriram, S.M., Kim, B.Y., and Kwon, Y.T. (2011). The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat. Rev. Mol. Cell Biol. 12, 735-747. https://doi.org/10.1038/nrm3217
  71. Stolz, A., Ernst, A., and Dikic, I. (2014). Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495-501. https://doi.org/10.1038/ncb2979
  72. Suber, T., Wei, J., Jacko, A.M., Nikolli, I., Zhao, Y., Zhao, J., and Mallampalli, R.K. (2017). SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3beta in lung epithelia. J. Biol. Chem. 292, 7452-7461. https://doi.org/10.1074/jbc.M116.771667
  73. Swatek, K.N., and Komander, D. (2016). Ubiquitin modifications. Cell Res. 26, 399-422. https://doi.org/10.1038/cr.2016.39
  74. Tasaki, T., Mulder, L.C., Iwamatsu, A., Lee, M.J., Davydov, I.V., Varshavsky, A., Muesing, M., and Kwon, Y.T. (2005). A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Molecular and cellular biology 25, 7120-7136. https://doi.org/10.1128/MCB.25.16.7120-7136.2005
  75. Tasaki, T., Sriram, S.M., Park, K.S., and Kwon, Y.T. (2012). The N-end rule pathway. Ann. Rev. Biochem. 81, 261-289. https://doi.org/10.1146/annurev-biochem-051710-093308
  76. Tasaki, T., Kim, S.T., Zakrzewska, A., Lee, B.E., Kang, M.J., Yoo, Y.D., Cha-Molstad, H.J., Hwang, J., Soung, N.K., Sung, K.S., et al. (2013). UBR box N-recognin-4 (UBR4)., an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy. Proc. Natl. Acad. Sci. USA 110, 3800-3805. https://doi.org/10.1073/pnas.1217358110
  77. Taylor, J.P., Brown, R.H., Jr., and Cleveland, D.W. (2016). Decoding ALS: from genes to mechanism. Nature 539, 197-206. https://doi.org/10.1038/nature20413
  78. Tomar, D., Prajapati, P., Sripada, L., Singh, K., Singh, R., Singh, A.K., and Singh, R. (2013). TRIM13 regulates caspase-8 ubiquitination, translocation to autophagosomes and activation during ER stress induced cell death. Biochim. Biophys. Acta 1833, 3134-3144. https://doi.org/10.1016/j.bbamcr.2013.08.021
  79. van Wijk, S.J., Fiskin, E., Putyrski, M., Pampaloni, F., Hou, J., Wild, P., Kensche, T., Grecco, H.E., Bastiaens, P., and Dikic, I. (2012). Fluorescence-based sensors to monitor localization and functions of linear and K63-linked ubiquitin chains in cells. Mol. Cell 47, 797-809. https://doi.org/10.1016/j.molcel.2012.06.017
  80. Wang, J., Kang, R., Huang, H., Xi, X., Wang, B., Wang, J., and Zhao, Z. (2014). Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 10, 766-784. https://doi.org/10.4161/auto.27954
  81. White, E. (2016). Autophagy and p53. Cold Spring Harb. Perspect Med. 6, a026120. https://doi.org/10.1101/cshperspect.a026120
  82. Wild, P., Farhan, H., McEwan, D.G., Wagner, S., Rogov, V.V., Brady, N.R., Richter, B., Korac, J., Waidmann, O., Choudhary, C., et al. (2011). Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228-233. https://doi.org/10.1126/science.1205405
  83. Wurzer, B., Zaffagnini, G., Fracchiolla, D., Turco, E., Abert, C., Romanov, J., and Martens, S. (2015). Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. eLife 4, e08941.
  84. Yamano, K., Matsuda, N., and Tanaka, K. (2016). The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation. EMBO Rep. 17, 300-316. https://doi.org/10.15252/embr.201541486
  85. Yau, R., and Rape, M. (2016). The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579-586. https://doi.org/10.1038/ncb3358
  86. Zaffagnini, G., and Martens, S. (2016). Mechanisms of selective autophagy. J. Mol. Biol. 428, 1714-1724. https://doi.org/10.1016/j.jmb.2016.02.004
  87. Zalckvar, E., Berissi, H., Eisenstein, M., and Kimchi, A. (2009). Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy 5, 720-722. https://doi.org/10.4161/auto.5.5.8625
  88. Zhang, X.D., Qi, L., Wu, J.C., and Qin, Z.H. (2013). DRAM1 regulates autophagy flux through lysosomes. PLoS one 8, e63245. https://doi.org/10.1371/journal.pone.0063245
  89. Zhang, H.T., Zeng, L.F., He, Q.Y., Tao, W.A., Zha, Z.G., and Hu, C.D. (2016). The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5. Biochim. Biophys. Acta 1863, 335-346. https://doi.org/10.1016/j.bbamcr.2015.12.001
  90. Zhang, Z., Wang, H., Ding, Q., Xing, Y., Xu, D., Xu, Z., Zhou, T., Qian, B., Ji, C., Pan, X., et al. (2017). The tumor suppressor p53 regulates autophagosomal and lysosomal biogenesis in lung cancer cells by targeting transcription factor EB. Biomed. Pharmacother. 89, 1055-1060. https://doi.org/10.1016/j.biopha.2017.02.103

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  96. Hyperphosphatemia-induced degradation of transcription factor EB exacerbates vascular calcification vol.1868, pp.3, 2017, https://doi.org/10.1016/j.bbadis.2021.166323