Sequestosome 1 Explained

Sequestosome-1 is a protein that in humans is encoded by the SQSTM1 gene.^{[1] [2] [3]} Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacting with GATA4 and targeting it for degradation, it can inhibit GATA-4 associated senescence and senescence-associated secretory phenotype.^[4]

Mutations in SQSTM1 are a common cause of Paget's disease of bone.^[5]

Interactions

Sequestosome 1 has been shown to interact with:

• MAP1LC3A,^[6]
• PRKCI,^[7]
• RAD23A,^[8]
• RIPK1,^[9]
• TRAF6^[10]
• TrkA,^{[11] [12] [13] [14]} and
• TrkB.^{[12] [13]}
• Nrf2^[15]

Further reading

• Geetha T, Wooten MW . Structure and functional properties of the ubiquitin binding protein p62 . FEBS Lett. . 512 . 1–3 . 19–24 . 2002 . 11852044 . 10.1016/S0014-5793(02)02286-X . 22029085 .
• Layfield R, Ciani B, Ralston SH, Hocking LJ, Sheppard PW, Searle MS, Cavey JR . Structural and functional studies of mutations affecting the UBA domain of SQSTM1 (p62) which cause Paget's disease of bone . Biochem. Soc. Trans. . 32 . Pt 5 . 728–30 . 2005 . 15493999 . 10.1042/BST0320728 . 22544044 .
• Michou L, Collet C, Laplanche JL, Orcel P, Cornélis F . Genetics of Paget's disease of bone . Joint Bone Spine . 73 . 3 . 243–8 . 2006 . 16574459 . 10.1016/j.jbspin.2005.05.009 .
• Park I, Chung J, Walsh CT, Yun Y, Strominger JL, Shin J . Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of Ser-59 in the lck unique N-terminal region . Proc. Natl. Acad. Sci. U.S.A. . 92 . 26 . 12338–42 . 1996 . 8618896 . 40352 . 10.1073/pnas.92.26.12338 . free .
• Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC . Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein . Biochemistry . 35 . 7 . 2157–67 . 1996 . 8652557 . 10.1021/bi9524124 .
• Vadlamudi RK, Joung I, Strominger JL, Shin J . p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins . J. Biol. Chem. . 271 . 34 . 20235–7 . 1996 . 8702753 . 10.1074/jbc.271.34.20235 . free .
• Marcus SL, Winrow CJ, Capone JP, Rachubinski RA . A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor . J. Biol. Chem. . 271 . 44 . 27197–200 . 1996 . 8910285 . 10.1074/jbc.271.44.27197 . free .
• Jallal B, Mossie K, Vasiloudis G, Knyazev P, Zachwieja J, Clairvoyant F, Schilling J, Ullrich A . The receptor-like protein-tyrosine phosphatase DEP-1 is constitutively associated with a 64-kDa protein serine/threonine kinase . J. Biol. Chem. . 272 . 18 . 12158–63 . 1997 . 9115287 . 10.1074/jbc.272.18.12158 . free .
• Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT . Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62 . Mol. Cell. Biol. . 18 . 5 . 3069–80 . 1998 . 9566925 . 110686 . 10.1128/mcb.18.5.3069.
• Vadlamudi RK, Shin J . Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein . FEBS Lett. . 435 . 2–3 . 138–42 . 1998 . 9762895 . 10.1016/S0014-5793(98)01021-7 . 3184369 . free .
• Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J . The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation . EMBO J. . 18 . 11 . 3044–53 . 1999 . 10356400 . 1171386 . 10.1093/emboj/18.11.3044 .
• Stumptner C, Heid H, Fuchsbichler A, Hauser H, Mischinger HJ, Zatloukal K, Denk H . Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent . Am. J. Pathol. . 154 . 6 . 1701–10 . 1999 . 10362795 . 1866621 . 10.1016/S0002-9440(10)65426-0 .
• Sudo T, Maruyama M, Osada H . p62 functions as a p38 MAP kinase regulator . Biochem. Biophys. Res. Commun. . 269 . 2 . 521–5 . 2000 . 10708586 . 10.1006/bbrc.2000.2333 .
• Sanz L, Diaz-Meco MT, Nakano H, Moscat J . The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway . EMBO J. . 19 . 7 . 1576–86 . 2000 . 10747026 . 310227 . 10.1093/emboj/19.7.1576 .
• Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J . The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor . J. Biol. Chem. . 276 . 11 . 7709–12 . 2001 . 11244088 . 10.1074/jbc.C000869200 . free .
• Kuusisto E, Salminen A, Alafuzoff I . Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies . NeuroReport . 12 . 10 . 2085–90 . 2001 . 11447312 . 10.1097/00001756-200107200-00009 . 21272705 .
• Laurin N, Brown JP, Lemainque A, Duchesne A, Huot D, Lacourcière Y, Drapeau G, Verreault J, Raymond V, Morissette J . Paget disease of bone: mapping of two loci at 5q35-qter and 5q31 . Am. J. Hum. Genet. . 69 . 3 . 528–43 . 2001 . 11473345 . 1235483 . 10.1086/322975 .
• Chang S, Kim JH, Shin J . p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4-induced PKCzeta inhibition . FEBS Lett. . 510 . 1–2 . 57–61 . 2002 . 11755531 . 10.1016/S0014-5793(01)03224-0 . 85579338 .
• Feng, Lifeng et al. “Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia” Theranostics vol. 7,7 1890-1900. 10 Apr. 2017, doi:10.7150/thno.19135

Notes and References

1. Joung I, Strominger JL, Shin J . Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain . Proc Natl Acad Sci U S A . 93 . 12 . 5991–5 . July 1996 . 8650207 . 39176 . 10.1073/pnas.93.12.5991 . 1996PNAS...93.5991J . free .
2. Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M . A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes . J Virol . 70 . 2 . 1143–53 . February 1996 . 8551575 . 189923 . 10.1128/JVI.70.2.1143-1153.1996.
3. Web site: Entrez Gene: SQSTM1 sequestosome 1.
4. Cassidy LD, Narita M . GATA get a hold on senescence . Science . 349 . 6255 . 1448–9 . 2015 . 26404812 . 10.1126/science.aad2501 . 2015Sci...349.1448C . 35805331 .
5. Layfield . R. . Ciani . B. . Ralston . S.H. . Hocking . L.J. . Sheppard . P.W. . Searle . M.S. . Cavey . J.R. . 2004-10-26 . Structural and functional studies of mutations affecting the UBA domain of SQSTM1 (p62) which cause Paget's disease of bone . Biochemical Society Transactions . 32 . 5 . 728–730 . 10.1042/bst0320728 . 15493999 . 22544044 . 0300-5127.
6. Shvets E, Fass E, Scherz-Shouval R, Elazar Z . The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes . J. Cell Sci. . 121 . Pt 16 . 2685–95 . 18653543 . 10.1242/jcs.026005 . August 2008. 2782335 .
7. Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT . Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62 . Mol. Cell. Biol. . 18 . 5 . 3069–80 . May 1998 . 9566925 . 110686 . 10.1128/mcb.18.5.3069.
8. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
9. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J . The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation . EMBO J. . 18 . 11 . 3044–53 . 10356400 . 1171386 . 10.1093/emboj/18.11.3044 . 1999 .
10. Sanz L, Diaz-Meco MT, Nakano H, Moscat J . The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway . EMBO J. . 19 . 7 . 1576–86 . April 2000 . 10747026 . 310227 . 10.1093/emboj/19.7.1576 .
11. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J . The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor . J. Biol. Chem. . 276 . 11 . 7709–12 . March 2001 . 11244088 . 10.1074/jbc.C000869200 . free .
12. Geetha T, Wooten MW . Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling . J. Biol. Chem. . 278 . 7 . 4730–9 . 12471037 . 10.1074/jbc.M208468200 . February 2003. free.
13. Jadhav T, Geetha T, Jiang J, Wooten MW . Identification of a consensus site for TRAF6/p62 polyubiquitination . Biochem. Biophys. Res. Commun. . 371 . 3 . 521–4 . 18457658 . 2474794 . 10.1016/j.bbrc.2008.04.138 . 2008 .
14. Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, Diaz-Meco MT, Moscat J . Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins . J. Biol. Chem. . 283 . 11 . 6783–9 . 18174161 . 10.1074/jbc.M709496200 . March 2008. free.
15. Feng, Lifeng et al. “Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia” Theranostics vol. 7,7 1890-1900. 10 Apr. 2017, doi:10.7150/thno.19135