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The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

Komatsu, Masaaki, Kurokawa, Hirofumi, Waguri, Satoshi, Taguchi, Keiko, Kobayashi, Akira, Ichimura, Yoshinobu, Sou, Yu-Shin, Ueno, Izumi, Sakamoto, Ayako, Tong, Kit I., Kim, Mihee, Nishito, Yasumasa, Iemura, Shun-ichiro, Natsume, Tohru, Ueno, Takashi, Kominami, Eiki, Motohashi, Hozumi, Tanaka, Keiji, Yamamoto, Masayuki·2010·Nature Cell Biology
DOI 10.1038/ncb2021
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Abstract

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

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  1. Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325–332 (2008). · DOI · Paper page
  2. Jung, H. S. et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324 (2008). · DOI · Paper page
  3. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). · DOI · Paper page
  4. Yorimitsu, T. & Klionsky, D. J. Autophagy: molecular machinery for self-eating. Cell Death Differ. 12 (Suppl. 2), 1542–1552 (2005). · DOI
  5. Platta, H. W. & Erdmann, R. Peroxisomal dynamics. Trends Cell Biol. 17, 474–484 (2007). · DOI
  6. Zhang, J. & Ney, P. A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 16, 939–946 (2009). · DOI · Paper page
  7. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nature Rev. Immunol. 7, 767–777 (2007). · DOI
  8. Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005). · DOI · Paper page
  9. Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007). · DOI · Paper page
  10. Nezis, I. P. et al. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J. Cell Biol. 180, 1065–1071 (2008). · DOI · Paper page
  11. Kuusisto, E., Salminen, A. & Alafuzoff, I. Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12, 2085–2090 (2001). · DOI
  12. Stumptner, C., Fuchsbichler, A., Heid, H., Zatloukal, K. & Denk, H. Mallory body — a disease-associated type of sequestosome. Hepatology 35, 1053–1062 (2002). · DOI
  13. Zatloukal, K. et al. p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160, 255–263 (2002). · DOI · Paper page
  14. Wakabayashi, N. et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nature Genet. 35, 238–245 (2003). · DOI
  15. Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W. & Diehl, J. A. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol. Cell. Biol. 24, 8477–8486 (2004). · DOI · Paper page
  16. Furukawa, M. & Xiong, Y. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol. Cell. Biol. 25, 162–171 (2005). · DOI
  17. Zhang, D. D., Lo, S. C., Cross, J. V., Templeton, D. J. & Hannink, M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24, 10941–10953 (2004). · DOI
  18. Dinkova-Kostova, A. T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl Acad. Sci. USA 99, 11908–11913 (2002). · DOI · Paper page
  19. Kobayashi, A. et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol. Cell. Biol. 26, 221–229 (2006). · DOI
  20. Holtzclaw, W. D., Dinkova-Kostova, A. T. & Talalay, P. Protection against electrophile and oxidative stress by induction of phase 2 genes: the quest for the elusive sensor that responds to inducers. Adv. Enzyme Regul. 44, 335–367 (2004). · DOI
  21. Kobayashi, M. & Yamamoto, M. Nrf2–Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv. Enzyme Regul. 46, 113–140 (2006). · DOI
  22. Komatsu, M. et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 23, 1977–1986 (2004). · DOI
  23. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M. & Hayes, J. D. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a 'tethering' mechanism: a two-site interaction model for the Nrf2–Keap1 complex. J. Biol. Chem. 281, 24756–24768 (2006). · DOI
  24. Tong, K. I. et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol. Cell. Biol. 27, 7511–7521 (2007). · DOI
  25. Seibenhener, M. L., Geetha, T. & Wooten, M. W. Sequestosome 1/p62 — More than just a scaffold. FEBS Lett. 581, 175–179 (2007). · DOI
  26. Lamark, T. et al. Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins. J. Biol. Chem. 278, 34568–34581 (2003). · DOI
  27. Ishii, T. et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem. 275, 16023–16029 (2000). · DOI
  28. Okawa, H. et al. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339, 79–88 (2006). · DOI
  29. Shibata, T. et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl Acad. Sci. USA 105, 13568–13573 (2008). · DOI · Paper page
  30. Matsumoto, N. et al. Comprehensive proteomics analysis of autophagy-deficient mouse liver. Biochem. Biophys. Res. Commun. 368, 643–649 (2008). · DOI
  31. Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin–proteasome pathway substrates. Mol. Cell 33, 517–527 (2009). · DOI · Paper page
  32. Otwinowski, A. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–325 (1997). · DOI · Paper page
  33. Vagin, A. & Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Crystallogr. 30, 1022–1025 (1997). · DOI
  34. Brunger, A. T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D Biol. Crystallogr. 54, 905–921 (1998). · DOI
  35. DeLano, W. L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002).
  36. Wallace, A. C., Laskowski, R. A. & Thornton, J. M. LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Eng. 8, 127–134 (1995). · DOI

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Metadata

Authors
Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.-S., Ueno, I., Sakamoto, A., Tong, K. I., Kim, M., Nishito, Y., Iemura, S.-I., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K., & Yamamoto, M.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2010-02-21
Volume
12
Issue
3
Pages
213-223
ISSN
  • 1465-7392
  • 1476-4679
DOI
10.1038/ncb2021
Cited by
2,288
References
18
Language
en
Licence
www.springer.com/tdm (tdm)

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