Emerging Paradigm of Crosstalk between Autophagy and the Ubiquitin-Proteasome System

  • Nam, Taewook (Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center, Yonsei University) ;
  • Han, Jong Hyun (Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center, Yonsei University) ;
  • Devkota, Sushil (Section of Cell and Developmental Biology, University of California San Diego) ;
  • Lee, Han-Woong (Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center, Yonsei University)
  • Received : 2017.09.26
  • Accepted : 2017.11.23
  • Published : 2017.12.31


Cellular protein homeostasis is maintained by two major degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Until recently, the UPS and autophagy were considered to be largely independent systems targeting proteins for degradation in the proteasome and lysosome, respectively. However, the identification of crucial roles of molecular players such as ubiquitin and p62 in both of these pathways as well as the observation that blocking the UPS affects autophagy flux and vice versa has generated interest in studying crosstalk between these pathways. Here, we critically review the current understanding of how the UPS and autophagy execute coordinated protein degradation at the molecular level, and shed light on our recent findings indicating an important role of an autophagy-associated transmembrane protein EI24 as a bridging molecule between the UPS and autophagy that functions by regulating the degradation of several E3 ligases with Really Interesting New Gene (RING)-domains.


Supported by : National Research Foundation of Korea (NRF)


  1. Araki, K., and Nagata, K. (2011). Protein folding and quality control in the ER. Cold Spring Harb. Perspect. Biol. 3, a007526.
  2. Ardley, H.C., and Robinson, P.A. (2005). E3 ubiquitin ligases. Essays Biochem. 41, 15-30.
  3. 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.
  4. Boucas, J., Fritz, C., Schmitt, A., Riabinska, A., Thelen, L., Peifer, M., Leeser, U., Nuernberg, P., Altmueller, J., Gaestel, M., et al. (2015). Label-free protein-RNA interactome znalysis identifies Khsrp signaling downstream of the p38/Mk2 kinase complex as a critical modulator of cell cycle progression. PLoS One 10, e0125745.
  5. Budenholzer, L., Cheng, C.L., Li, Y., and Hochstrasser, M. (2017). Proteasome structure and Assembly. J. Mol. Biol. 429, 3500-3524.
  6. 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.
  7. Cha-Molstad, H., Yu, J.E., Feng, Z., Lee, S.H., Kim, J.G., Yang, P., Han, B., Sung, K.W., Yoo, Y.D., Hwang, J., et al. (2017). p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat. Commun. 8, 102.
  8. Chan, N.C., Salazar, A.M., Pham, A.H., Sweredoski, M.J., Kolawa, N.J., Graham, R.L., Hess, S., and Chan, D.C. (2011). Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726-1737.
  9. Choi, J.M., Devkota, S., Sung, Y.H., and Lee, H.W. (2013). EI24 regulates epithelial-to-mesenchymal transition and tumor progression by suppressing TRAF2-mediated NF-kappaB activity. Oncotarget 4, 2383-2396.
  10. Chude, C.I., and Amaravadi, R.K. (2017). Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int. J. Mol. Sci. 18.
  11. Ciechanover, A. (2005). Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol. 6, 79-87.
  12. Cohen-Kaplan, V., Livneh, I., Avni, N., Cohen-Rosenzweig, C., and Ciechanover, A. (2016). The ubiquitin-proteasome system and autophagy: coordinated and independent activities. Int. J. Biochem. Cell. Biol. 79, 403-418.
  13. Collins, G.A., and Goldberg, A.L. (2017). The logic of the 26S proteasome. Cell 169, 792-806.
  14. Crick, F. (1970). Central dogma of molecular biology. Nature 227, 561-563.
  15. Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P.R., Gasco, M., Garrone, O., Crook, T., and Ryan, K.M. (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121-134.
  16. de Bie, P., and Ciechanover, A. (2011). Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and nonproteolytic mechanisms. Cell Death Differ. 18, 1393-1402.
  17. Devkota, S., Sung, Y.H., Choi, J.M., Lee, J., Ha, N.Y., Kim, H., Cho, B.C., Song, J., and Lee, H.W. (2012). Ei24-deficiency attenuates protein kinase Calpha signaling and skin carcinogenesis in mice. Int. J. Biochem. Cell Biol. 44, 1887-1896.
  18. Devkota, S., Jeong, H., Kim, Y., Ali, M., Roh, J.I., Hwang, D., and Lee, H.W. (2016). Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases. Autophagy 12, 2038-2053.
  19. Dikic, I. (2017). Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 86, 193-224.
  20. Feng, Y., He, D., Yao, Z., and Klionsky, D.J. (2014). The machinery of macroautophagy. Cell Re.s 24, 24-41.
  21. Gomes, L.C., Di Benedetto, G., and Scorrano, L. (2011). During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589-598.
  22. Groll, M. and Huber, R. (2003). Substrate access and processing by the 20S proteasome core particle. Int. J. Biochem. Cell Biol. 35, 606-616.
  23. Gurusamy, N., Lekli, I., Gherghiceanu, M., Popescu, L.M., and Das, D.K. (2009). BAG-1 induces autophagy for cardiac cell survival. Autophagy 5, 120-121.
  24. Hershko, A. (2005). The ubiquitin system for protein degradation and some of its roles in the control of the cell-division cycle (Nobel lecture). Angew. Chem. Int. Ed. Engl. 44, 5932-5943.
  25. Hershko, A., Heller, H., Elias, S., and Ciechanover, A. (1983). Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258, 8206-8214.
  26. Hewitt, G., Carroll, B., Sarallah, R., Correia-Melo, C., Ogrodnik, M., Nelson, G., Otten, E.G., Manni, D., Antrobus, R., Morgan, B.A., et al. (2016). SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 12, 1917-1930.
  27. Houck, S.A., Ren, H.Y., Madden, V.J., Bonner, J.N., Conlin, M.P., Janovick, J.A., Conn, P.M., and Cyr, D.M. (2014). Quality control autophagy degrades soluble ERAD-resistant conformers of the misfolded membrane protein GnRHR. Mol. Cell 54, 166-179.
  28. Hwang, D., Stephanopoulos, G., and Chan, C. (2004). Inverse modeling using multi-block PLS to determine the environmental conditions that provide optimal cellular function. Bioinformatics 20, 487-499.
  29. Jiang, T., Harder, B., Rojo de la Vega, M., Wong, P.K., Chapman, E. ,and Zhang, D.D. (2015). p62 links autophagy and Nrf2 signaling. Free Radic. Biol. Med. 88, 199-204.
  30. Kirkin, V., McEwan, D.G., Novak, I., and Dikic, I. (2009). A role for ubiquitin in selective autophagy. Mol. Cell 34, 259-269.
  31. Klionsky, D.J., Abeliovich, H., Agostinis, P., Agrawal, D.K., Aliev, G., Askew, D.S., Baba, M., Baehrecke, E.H., Bahr, B.A., Ballabio, A., et al. (2008). Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151-175.
  32. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434.
  33. Komatsu, M., Waguri, S., Koike, M., Sou, Y.S., Ueno, T., Hara, T., Mizushima, N., Iwata, J., Ezaki, J., Murata, S., et al. (2007). Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149-1163.
  34. Korolchuk, V.I., Mansilla, A., Menzies, F.M., and Rubinsztein, D.C. (2009a). Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517-527.
  35. Korolchuk, V.I., Menzies, F.M., and Rubinsztein, D.C. (2009b). A novel link between autophagy and the ubiquitin-proteasome system. Autophagy 5, 862-863.
  36. Korolchuk, V.I., Menzies, F.M., and Rubinsztein, D.C. (2010). Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. 584, 1393-1398.
  37. Kriegenburg, F., Jakopec, V., Poulsen, E.G., Nielsen, S.V., Roguev, A., Krogan, N., Gordon, C., Fleig, U., and Hartmann-Petersen, R. (2014). A chaperone-assisted degradation pathway targets kinetochore proteins to ensure genome stability. PLoS Genet. 10, e1004140.
  38. Kwon, Y.T., and Ciechanover, A. (2017). The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 42, 873-886.
  39. Labbadia, J., and Morimoto, R.I. (2015). The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435-464.
  40. Lamb, C.A., Yoshimori, T., and Tooze, S.A. (2013). The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14, 759-774.
  41. Lee, J., Giordano, S., and Zhang, J. (2012). Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441, 523-540.
  42. Lilienbaum, A. (2013). Relationship between the proteasomal system and autophagy. Int. J. Biochem. Mol. Biol. 4, 1-26.
  43. Liu, W.J., Ye, L., Huang, W.F., Guo, L.J., Xu, Z.G., Wu, H.L., Yang, C., and Liu, H.F. (2016). p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol. Biol. Lett. 21, 29.
  44. Livneh, I., Cohen-Kaplan, V., Cohen-Rosenzweig, C., Avni, N., and Ciechanover, A. (2016). The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res. 26, 869-885.
  45. 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.
  46. Metzger, M.B., Pruneda, J.N., Klevit, R.E., and Weissman, A.M. (2014). RING-type E3 ligases: master manipulators of E2 ubiquitinconjugating enzymes and ubiquitination. Biochim. Biophys. Acta 1843, 47-60.
  47. Meusser, B., Hirsch, C., Jarosch, E., and Sommer, T. (2005). ERAD: the long road to destruction. Nat. Cell Biol. 7, 766-772.
  48. Mizushima, N. (2007). Autophagy: process and function. Genes Dev. 21, 2861-2873.
  49. Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830.
  50. Moreau, K., Renna, M., and Rubinsztein, D.C. (2013). Connections between SNAREs and autophagy. Trends Biochem. Sci. 38, 57-63.
  51. Nakatogawa, H. (2013). Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem. 55, 39-50.
  52. Nandi, D., Tahiliani, P., Kumar, A., and Chandu, D. (2006). The ubiquitin-proteasome system. .J Biosci. 31, 137-155.
  53. Ohsumi, Y. (2014). Historical landmarks of autophagy research. Cell Res. 24, 9-23.
  54. 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.
  55. Park, C., and Cuervo, A.M. (2013). Selective autophagy: talking with the UPS. Cell Biochem. Biophys. 67, 3-13.
  56. Park, M.C., Jeong, H., Son, S.H., Kim, Y., Han, D., Goughnour, P.C., Kang, T., Kwon, N.H., Moon, H.E., Paek, S.H., et al. (2016). Novel morphologic and genetic analysis of cancer cells in a 3D microenvironment identifies STAT3 as a regulator of tumor permeability barrier function. Cancer Res. 76, 1044-1054.
  57. Pickart, C.M. (2004). Back to the future with ubiquitin. Cell 116, 181-190.
  58. Ravikumar, B., Sarkar, S., Davies, J.E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z.W., Jimenez-Sanchez, M., Korolchuk, V.I., Lichtenberg, M., Luo, S., et al. (2010). Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383-1435.
  59. Ruan, L., Zhou, C., Jin, E., Kucharavy, A., Zhang, Y., Wen, Z., Florens, L., and Li, R. (2017). Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature 543, 443-446.
  60. Russell, R.C., Yuan, H.X., and Guan, K.L. (2014). Autophagy regulation by nutrient signaling. Cell Res. 24, 42-57.
  61. Schmidt, M., and Finley, D. (2014). Regulation of proteasome activity in health and disease. Biochim. Biophys. Acta 1843, 13-25.
  62. Schreiber, A., and Peter, M. (2014). Substrate recognition in selective autophagy and the ubiquitin-proteasome system. Biochim. Biophys. Acta 1843, 163-181.
  63. Shen, Y.F., Tang, Y., Zhang, X.J., Huang, K.X., and Le, W.D. (2013). Adaptive changes in autophagy after UPS impairment in Parkinson's disease. Acta Pharmacol. Sin. 34, 667-673.
  64. 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.
  65. Streich, F.C., Jr., and Lima, C.D. (2014). Structural and functional insights to ubiquitin-like protein conjugation. Annu. Rev. Biophys. 43, 357-379.
  66. Suzuki, K., and Ohsumi, Y. (2007). Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 581, 2156-2161.
  67. Tai, H.C., and Schuman, E.M. (2008). Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat. Rev. Neurosci. 9, 826-838.
  68. Tang, F., Wang, B., Li, N., Wu, Y., Jia, J., Suo, T., Chen, Q., Liu, Y.J., and Tang, J. (2011). RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates autophagy through interaction with BNIP1. PLoS One 6, e24367.
  69. Thrower, J.S., Hoffman, L., Rechsteiner, M., and Pickart, C.M. (2000). Recognition of the polyubiquitin proteolytic signal. EMBO J. 19, 94-102.
  70. Tooze, S.A., and Dikic, I. (2016). Autophagy captures the nobel prize. Cell 167, 1433-1435.
  71. Wang, C., and Wang, X. (2015). The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity. Biochim. Biophys. Acta 1852, 188-194.
  72. Watson, J.D., and Crick, F.H. (2003). Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. 1953. Rev. Invest. Clin. 55, 108-109.
  73. Wei, Y., Pattingre, S., Sinha, S., Bassik, M., and Levine, B. (2008). JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell 30, 678-688.
  74. Youle, R.J., and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12, 9-14.
  75. Zhao, J., Brault, J.J., Schild, A., Cao, P., Sandri, M., Schiaffino, S., Lecker, S.H., and Goldberg, A.L. (2007). FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472-483.
  76. Zhao, Y.G., Zhao, H., Miao, L., Wang, L., Sun, F., and Zhang, H. (2012). The p53-induced gene Ei24 is an essential component of the basal autophagy pathway. J. Biol. Chem. 287, 42053-42063.
  77. Zhao, B., Qiang, L., Joseph, J., Kalyanaraman, B., Viollet, B., and He, Y.Y. (2016). Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival. Genes Dis. 3, 82-87.
  78. Zhou, J., Zhang, Y., Qi, J., Chi, Y., Fan, B., Yu, J.Q., and Chen, Z. (2014). E3 ubiquitin ligase CHIP and NBR1-mediated selective autophagy protect additively against proteotoxicity in plant stress responses. PLoS Genet. 10, e1004116.

Cited by

  1. Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis pp.1607-8438, 2018,
  2. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines vol.9, pp.1664-3224, 2018,