Current Cancer Drug Targets

Author(s): Shunbin Ning and Ling Wang*

DOI: 10.2174/1568009618666181016164920

The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers

Page: [468 - 478] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

The multifunctional signaling hub p62 is well recognized as a ubiquitin sensor and a selective autophagy receptor. As a ubiquitin sensor, p62 promotes NFκB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 sorts ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy. Targeting p62-mediated autophagy may represent a promising strategy for clinical interventions of different cancers. In this review, we summarize the transcriptional and post-translational regulation of p62, and its mechanistic roles in cancers, with the emphasis on its roles in regulation of DNA damage response and its connection to the cGAS-STING-mediated antitumor immune response, which is promising for cancer vaccine design.

Keywords: p62, autophagy, ubiquitination, ROS, antitumor immune response, cancer vaccine design.

Graphical Abstract

[1]
Wooten, M.W.; Geetha, T.; Babu, J.R.; Seibenhener, M.L.; Peng, J.; Cox, N.; Diaz-Meco, M-T.; Moscat, J. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem., 2008, 283(11), 6783-6789.
[2]
Moscat, J.; Karin, M.; Diaz-Meco, M.T. p62 in cancer: Signaling adaptor beyond autophagy. Cell, 2016, 167(3), 606-609.
[3]
Moscat, J.; Diaz-Meco, M.T. p62: A versatile multitasker takes on cancer. Trends Biochem. Sci., 2012, 37(6), 230-236.
[4]
Nezis, I.P.; Stenmark, H. p62 at the Interface of Autophagy, Oxidative Stress Signaling, and Cancer. Antioxid. Redox Signal., 2011, 17(5), 786-793.
[5]
Bitto, A.; Lerner, C.A.; Nacarelli, T.; Crowe, E.; Torres, C.; Sell, C. p62/SQSTM1 at the interface of aging, autophagy, and disease. Age , 2014, 36(3), 9626.
[6]
Xiao, B.; Deng, X.; Lim, G.G.Y.; Zhou, W.; Saw, W-T.; Zhou, Z.D.; Lim, K-L.; Tan, E-K. p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization. Biochim. Biophys. Acta (BBA) –. Mol. Cell Res, 2017, 1864(7), 1308-1317.
[7]
Nakamura, K.; Kimple, A.J.; Siderovski, D.P.; Johnson, G.L. PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation. J. Biol. Chem., 2010, 285(3), 2077-2089.
[8]
Itakura, E.; Mizushima, N. p62 targeting to the autophagosome formation site requires self-oligomerization but not LC3 binding. J. Cell Biol., 2011, 192(1), 17-27.
[9]
Feng, Y.; Zhao, H.; Luderer, H.F.; Epple, H.; Faccio, R.; Ross, F.P.; Teitelbaum, S.L.; Longmore, G.D. The LIM protein, LIMD1, regulates AP-1 activation through an interaction with TRAF6 to influence osteoclast development. J. Biol. Chem., 2007, 282(1), 39-48.
[10]
Feng, Y.; Longmore, G.D. The LIM protein ajuba influences interleukin-1-induced NF-κB activation by affecting the assembly and activity of the protein kinase Cζ/p62/TRAF6 signaling complex. Mol. Cell. Biol., 2005, 25(10), 4010-4022.
[11]
Jain, A.; Lamark, T.; Sjøttem, E. Bowitz, Larsen, K.; Atesoh Awuh, J.; Øvervatn, A.; McMahon, M.; Hayes, J.D.; Johansen, T. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem., 2010, 285(29), 22576-22591.
[12]
Duran, A.; Linares, J.F.; Galvez, A.S.; Wikenheiser, K.; Flores, J.M.; Diaz-Meco, M.T.; Moscat, J. The signaling adaptor p62 is an important NF-κB mediator in tumorigenesis. Cancer Cell, 2008, 13(4), 343-354.
[13]
Zhong, Z.; Umemura, A.; Sanchez-Lopez, E.; Liang, S.; Shalapour, S.; Wong, J.; He, F.; Boassa, D.; Perkins, G.; Ali, S.R.; McGeough, M.D. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell, 2016, 164(5), 896-910.
[14]
Thompson, H.G.R.; Harris, J.W.; Wold, B.J.; Lin, F.; Brody, J.P. p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. Oncogene, 2003, 22(15), 2322-2333.
[15]
Yang, S.; Qiang, L.; Sample, A.; Shah, P.; He, Y.Y. NF-kappaB signaling activation induced by chloroquine requires autophagosome, p62 protein, and c-Jun N-terminal kinase (JNK) signaling and promotes tumor cell resistance. J. Biol. Chem., 2017, 292(8), 3379-3388.
[16]
B’chir, W.; Maurin, A-C.; Carraro, V.; Averous, J.; Jousse, C.; Muranishi, Y.; Parry, L.; Stepien, G.; Fafournoux, P.; Bruhat, A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res., 2013, 41(16), 7683-7699.
[17]
Huang, H.; Zhu, J.; Li, Y.; Zhang, L.; Gu, J.; Xie, Q.; Jin, H.; Che, X.; Li, J.; Huang, C.; Chen, L.C. Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells. Autophagy, 2016, 12(10), 1687-1703.
[18]
Poillet-Perez, L.; Despouy, G.; Delage-Mourroux, R.; Boyer-Guittaut, M. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol., 2015, 4, 184-192.
[19]
Mitsuishi, Y.; Motohashi, H.; Yamamoto, M. The Keap1–Nrf2 system in cancers: Stress response and anabolic metabolism. Front. Oncol., 2012, 2, 200.
[20]
Kansanen, E.; Kuosmanen, S.M.; Leinonen, H.; Levonen, A-L. The keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol., 2013, 1(1), 45-49.
[21]
Taguchi, K.; Fujikawa, N.; Komatsu, M.; Ishii, T.; Unno, M.; Akaike, T.; Motohashi, H.; Yamamoto, M. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl. Acad. Sci. , 2012, 109(34), 13561-13566.
[22]
Bryan, H.K.; Olayanju, A.; Goldring, C.E.; Park, B.K. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem. Pharmacol., 2013, 85(6), 705-717.
[23]
Filomeni, G.; De Zio, D.; Cecconi, F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ., 2015, 22(3), 377-388.
[24]
Ichimura, Y.; Waguri, S.; Sou, Y.S.; Kageyama, S.; Hasegawa, J.; Ishimura, R.; Saito, T.; Yang, Y.; Kouno, T.; Fukutomi, T.; Hoshii, T. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell, 2013, 51(5), 618-631.
[25]
Fan, W.; Tang, Z.; Chen, D.; Moughon, D.; Ding, X.; Chen, S.; Zhu, M.; Zhong, Q. Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy, 2010, 6(5), 614-621.
[26]
Komatsu, M.; Ichimura, Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett., 2010, 584(7), 1374-1378.
[27]
Gruhne, B.; Sompallae, R.; Masucci, M.G. Three epstein-barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints. Oncogene, 2009, 28(45), 3997-4008.
[28]
Cerimele, F.; Battle, T.; Lynch, R.; Frank, D.A.; Murad, E.; Cohen, C.; Macaron, N.; Sixbey, J.; Smith, K.; Watnick, R.S.; Eliopoulos, A. Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt’s lymphoma. Proc. Natl. Acad. Sci. USA, 2005, 102(1), 175-179.
[29]
Gruhne, B.; Sompallae, R.; Marescotti, D.; Kamranvar, S.A.; Gastaldello, S.; Masucci, M.G. The epstein-barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc. Natl. Acad. Sci. , 2009, 106(7), 2313-2318.
[30]
Raab-Traub, N. Epstein-Barr virus in the pathogenesis of NPC. Semin. Cancer Biol., 2002, 12(6), 431-441.
[31]
Kim, S.M.; Hur, D.Y.; Hong, S.W.; Kim, J.H. EBV-encoded EBNA1 regulates cell viability by modulating miR34a-NOX2-ROS signaling in gastric cancer cells. Biochem. Biophys. Res. Commun., 2017, 494(3-4), 550-555.
[32]
Yang, J.; Peng, H.; Xu, Y.; Xie, X.; Hu, R. SQSTM1/p62 (sequestosome 1) senses cellular ubiquitin stress through E2-mediated ubiquitination. Autophagy, 2018, 14(6), 1072-1073.
[33]
Tan, J.M.M.; Wong, E.S.P.; Dawson, V.L.; Dawson, T.; Lim, K-L. Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy, 2008, 4(2), 251-253.
[34]
Shaid, S.; Brandts, C.H.; Serve, H.; Dikic, I. Ubiquitination and selective autophagy. Cell Death Differ., 2012, 20, 21.
[35]
Peng, H.; Yang, J.; Li, G.; You, Q.; Han, W.; Li, T.; Gao, D.; Xie, X.; Lee, B.H.; Du, J.; Hou, J.; Zhang, T.; Rao, H.; Huang, Y.; Li, Q.; Zeng, R.; Hui, L.; Wang, H.; Xia, Q.; Zhang, X.; He, Y.; Komatsu, M.; Dikic, I.; Finley, D.; Hu, R. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res., 2017, 27, 657.
[36]
Lippai, M.; Low, P. The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. BioMed Res. Int., 2014, 2014832704
[37]
Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Overvatn, A.; Bjorkoy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem., 2007, 282.
[38]
Bjorkoy, G.; Lamark, T.; Brech, A. Outzen. H.; Perander, M.; Overvatn, A.; Stenmark, H.; Johansen, T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol., 2005, 171.
[39]
Johansen, T.; Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy, 2011, 7(3), 279-296.
[40]
Lamark, T.; Kirkin, V.; Dikic, I.; Johansen, T. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle, 2009, 8(13), 1986-1990.
[41]
Rogov, V.; Dotsch, V.; Johansen, T.; Kirkin, V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell, 2014, 53(2), 167-178.
[42]
Zaffagnini, G.; Martens, S. Mechanisms of selective autophagy. J. Mol. Biol., 2016, 428(9Part A), 1714-1724.
[43]
Wang, L.; Riggs, K.; Kohne, C.; Yohanon, J.U.; Foxler, D.E.; Sharp, T.V.; Moorman, J.P.; Yao, Z.Q.; Ning, S. LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death. Oncotarget, 2018, 9(5), 6282-6297.
[44]
Gelino, S.; Hansen, M. Autophagy-an emerging anti-aging mechanism. J. Clin. Exper. Pathol.,, 2012, (Suppl 4), 006.
[45]
Hewitt, G.; Carroll, B.; Sarallah, R.; Correia-Melo, C.; Ogrodnik, M.; Nelson, G.; Otten, E.G.; Manni, D.; Antrobus, R.; Morgan, B.A.; von Zglinicki, T. SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy, 2016, 12(10), 1917-1930.
[46]
Du, Y.; Wooten, M.C.; Gearing, M.; Wooten, M.W. Age-associated oxidative damage to the p62 promoter: Implications for Alzheimer disease. Free Radic. Biol. Med., 2009, 46(4), 492-501.
[47]
Du, Y.; Wooten, M.C.; Wooten, M.W. Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol. Dis., 2009, 35(2), 302-310.
[48]
Lee, Y.; Chou, T.F.; Pittman, S.K.; Keith, A.L.; Razani, B.; Weihl, C.C. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep., 2017, 19(1), 188-202.
[49]
Lee, Y.; Weihl, C.C. Regulation of SQSTM1/p62 via UBA domain ubiquitination and its role in disease. Autophagy, 2017, 13(9), 1615-1616.
[50]
Pan, J.A.; Sun, Y.; Jiang, Y.P.; Bott, A.J.; Jaber, N.; Dou, Z.; Yang, B.; Chen, J.S.; Catanzaro, J.M.; Du, C.; Ding, W.X.; Diaz-Meco, M.T.; Moscat, J.; Ozato, K.; Lin, R.Z.; Zong, W.X. TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Mol. Cell, 2016, 61(5), 720-733. (a) Song, P.; Li, S.; Wu, H.; Gao, R.; Rao, G.; Wang, D.; Chen, Z.; Ma, B.; Wang, H.; Sui, N.; Deng, H; Parkin promotes proteasomal degradation of p62: Implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson’s disease. Protein Cell, 2016, 7(2), 114-129.
[51]
Hayashi, K.; Dan, K.; Goto, F.; Tshuchihashi, N.; Nomura, Y.; Fujioka, M.; Kanzaki, S.; Ogawa, K. The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress. Cell. Signal., 2015, 27(2), 382-393.
[52]
Jiang, X.; Bao, Y.; Liu, H.; Kou, X.; Zhang, Z.; Sun, F.; Qian, Z.; Lin, Z.; Li, X.; Liu, X.; Jiang, L. VPS34 stimulation of p62 phosphorylation for cancer progression. Oncogene, 2017, 36, 6850.
[53]
Lim, J.; Lachenmayer, M.L.; Wu, S.; Liu, W.; Kundu, M.; Wang, R.; Komatsu, M.; Oh, Y.J.; Zhao, Y.; Yue, Z. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet., 2015, 11(2)e1004987
[54]
Matsumoto, G.; Wada, K.; Okuno, M.; Kurosawa, M.; Nukina, N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell, 2011, 44(2), 279-289.
[55]
Linares, J.F.; Amanchy, R.; Diaz-Meco, M.T.; Moscat, J. Phosphorylation of p62 by cdk1 Controls the Timely Transit of Cells through Mitosis and Tumor Cell Proliferation. Mol. Cell. Biol., 2011, 31(1), 105-117.
[56]
Prabakaran, T.; Bodda, C.; Krapp, C.; Zhang, B.C.; Christensen, M.H.; Sun, C.; Reinert, L.; Cai, Y.; Jensen, S.B.; Skouboe, M.K.; and Nyengaard, J.R. Attenuation of cGASâ€STING signaling is mediated by a p62/SQSTM1â€dependent autophagy pathway activated by TBK1. EMBO J., 2018, 37e97858
[57]
Deretic, V.; Saitoh, T.; Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol., 2013, 13(10), 722-737.
[58]
Galluzzi, L.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravoâ€San Pedro, J.M.; Cecconi, F.; Choi, A.M.; Chu, C.T.; Codogno, P.; Colombo, M.I.; Cuervo, A.M. Molecular definitions of autophagy and related processes. EMBO J., 2017, 36(13), 1811-1836.
[59]
Kaushik, S.; Cuervo, A.M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol., 2012, 22(8), 407-417.
[60]
White, E. The role for autophagy in cancer. J. Clin. Invest., 2015, 125(1), 42-46.
[61]
Lorin, S.; Hamaï, A.; Mehrpour, M.; Codogno, P. Autophagy regulation and its role in cancer. Semin. Cancer Biol., 2013, 23(5), 361-379.
[62]
Santana-Codina, N.; Mancias, J.D.; Kimmelman, A.C. The role of autophagy in cancer. Ann. Rev. Cancer Biol., 2017, 1(1), 19-39.
[63]
Amaravadi, R.; Kimmelman, A.C.; White, E. Recent insights into the function of autophagy in cancer. Genes Dev., 2016, 30(17), 1913-1930.
[64]
Czarny, P.; Pawlowska, E.; Bialkowska-Warzecha, J.; Kaarniranta, K.; Blasiak, J. Autophagy in DNA damage response. Int. J. Mol. Sci., 2015, 16(2), 2641-2662.
[65]
Pankiv, S.; Lamark, T.; Bruun, J-A.; Øvervatn, A.; Bjørkøy, G.; Johansen, T. Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J. Biol. Chem., 2010, 285(8), 5941-5953.
[66]
Liu, Y.; Levine, B. Autosis and autophagic cell death: The dark side of autophagy. Cell Death Differ., 2015, 22, 367.
[67]
Farre, J-C.; Subramani, S. Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat. Rev. Mol. Cell Biol., 2016, 17(9), 537-552.
[68]
Sparrer, K.M.J.; Gack, M.U. TRIM proteins: New players in virus-induced autophagy. PLoS Pathog., 2018, 14(2)e1006787
[69]
Rea, S.L.; Walsh, J.P.; Layfield, R.; Ratajczak, T.; Xu, J. New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of paget’s disease of bone. Endocr. Rev., 2013, 34(4), 501-524.
[70]
Birgisdottir, Å.B.; Lamark, T.; Johansen, T. The LIR motif – crucial for selective autophagy. J. Cell Sci., 2013, 126(15), 3237-3247.
[71]
Khaminets, A.; Behl, C.; Dikic, I. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol., 2016, 26(1), 6-16.
[72]
Kraft, C.; Peter, M.; Hofmann, K. Selective autophagy: Ubiquitin-mediated recognition and beyond. Nat. Cell Biol., 2010, 12, 836.
[73]
Myeku, N.; Figueiredo-Pereira, M.E. Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J. Biol. Chem., 2011, 286(25), 22426-22440.
[74]
Schreiber, A.; Peter, M. Substrate recognition in selective autophagy and the ubiquitin-proteasome system. Biochim. Biophys. Acta, 2014, 1843(1), 163-181.
[75]
Isakson, P.; Holland, P.; Simonsen, A. The role of ALFY in selective autophagy. Cell Death Differ., 2013, 20(1), 12-20.
[76]
Rogov, V.; Kirkin, V. Chapter 4 -Selective autophagy: Role of ubiquitin and ubiquitin-like proteins in targeting protein aggregates, organelles, and pathogens. In: Autophagy: cancer, other pathologies, inflammation, immunity, infection, and aging. Edited by Hayat MA, vol. 4. Amsterdam: Academic Press; , 2014, pp. 59-88.
[77]
Yoo, S-M.; Jung, Y-K. A molecular approach to mitophagy and mitochondrial dynamics. Mol. Cells, 2018, 41(1), 18-26.
[78]
Liu, W.J.; Ye, L.; Huang, W.F.; Guo, L.J.; Xu, Z.G.; Wu, H.L.; Yang, C.; Liu, H.F. p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation. Cell. Mol. Biol. Lett., 2016, 21(1), 29.
[79]
Cohen-Kaplan, V.; Ciechanover, A.; Livneh, I. p62 at the crossroad of the ubiquitin-proteasome system and autophagy. Oncotarget, 2016, 7(51), 83833-83834.
[80]
Demishtein, A.; Fraiberg, M.; Berko, D.; Tirosh, B.; Elazar, Z.; Navon, A. SQSTM1/p62-mediated autophagy compensates for loss of proteasome polyubiquitin recruiting capacity. Autophagy, 2017, 13(10), 1697-1708.
[81]
Su, H.; Wang, X. p62 Stages an Interplay between the ubiquitin-proteasome system and autophagy in the heart of defense against proteotoxic stress. Trends Cardiovasc. Med., 2011, 21(8), 224-228.
[82]
Babu, J.R.; Geetha, T.; Wooten, M.W. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem., 2005, 94(1), 192-203.
[83]
Cohen-Kaplan, V.; Livneh, I.; Avni, N.; Fabre, B.; Ziv, T.; Kwon, Y.T.; Ciechanover, A. p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc. Natl. Acad. Sci., 2016, 113(47), E7490-E7499.
[84]
Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem., 2017, 86, 193-224.
[85]
Korolchuk, V.I.; Menzies, F.M.; Rubinsztein, D.C. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett., 2010, 584(7), 1393-1398.
[86]
Wang, X.J.; Yu, J.; Wong, S.H.; Cheng, A.S.; Chan, F.K.; Ng, S.S.; Cho, C.H.; Sung, J.J.; Wu, W.K. A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy. Autophagy, 2013, 9(10), 1500-1508.
[87]
Matsumoto, G.; Shimogori, T.; Hattori, N.; Nukina, N. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum. Mol. Genet., 2015, 24(15), 4429-4442.
[88]
Geetha, T.; Wooten, M.W. Structure and functional properties of the ubiquitin binding protein p62. FEBS Lett., 2002, 512(1-3), 19-24.
[89]
Chen, M.; Meng, Q.; Qin, Y.; Liang, P.; Tan, P.; He, L.; Zhou, Y.; Chen, Y.; Huang, J.; Wang, R.F.; Cui, J. TRIM14 Inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses. Mol. Cell, 2016, 64(1), 105-119.
[90]
Sanz, L.; Diaz-Meco, M.T.; Nakano, H.; Moscat, J. The atypical PKC-interacting protein p62 channels NFâ€ÎºB activation by the IL1-TRAF6 pathway. EMBO J., 2000, 19(7), 1576-1586.
[91]
Sanz, L.; Sanchez, P.; Lallena, M.J.; Diaz-Meco, M.T.; Moscat, J. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J., 1999, 18(11), 3044-3053.
[92]
Moscat, J.; Diaz-Meco, M.T. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell, 2009, 137(6), 1001-1004.
[93]
Wooten, M.W.; Geetha, T.; Seibenhener, M.L.; Babu, J.R.; Diaz-Meco, M.T.; Moscat, J. The p62 scaffold regulates nerve growth factor-induced NF-κB activation by influencing TRAF6 polyubiquitination. J. Biol. Chem., 2005, 280(42), 35625-35629.
[94]
Zotti, T.; Scudiero, I.; Settembre, P.; Ferravante, A.; Mazzone, P.; D’Andrea, L.; Reale, C.; Vito, P.; Stilo, R. TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1. Mol. Immunol., 2014, 58(1), 27-31.
[95]
Xiao-Yu, Y.; Yu, Z.; Juan-Juan, Z.; Li-Chao, Z.; Ya-Nan, L.; Yao, W.; Ya-Nan, X.; Sheng-Yao, L.; Jing, S.; Lian-Kun, S. p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells. Cancer Sci., 2017, 108(7), 1405-1413.
[96]
Puissant, A.; Fenouille, N.; Auberger, P. When autophagy meets cancer through p62/SQSTM1. Am. J. Cancer Res., 2012, 2(4), 397-413.
[97]
Umemura, A.; He, F.; Taniguchi, K.; Nakagawa, H.; Yamachika, S.; Font-Burgada, J.; Zhong, Z.; Subramaniam, S.; Raghunandan, S.; Duran, A.; Linares, J.F. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell, 2016, 29(6), 935-948.
[98]
Roodman, G.D.; Hiruma, Y.; Kurihara, N. p62: A potential target for blocking microenvironmental support of myeloma. Clin. Lymphoma Myeloma, 2009, 9, S25-S26.
[99]
Rybstein, M.D.; Bravo-San Pedro, J.M.; Kroemer, G.; Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol., 2018, 20(3), 243-251.
[100]
Marinković, M.; Šprung, M.; Buljubašić, M.; Novak, I. Autophagy modulation in cancer: current knowledge on action and therapy. Oxid. Med. Cell. Longev., 2018, 2018, 18.
[101]
Wilde, L.; Tanson, K.; Curry, J.; Martinez-Outschoorn, U. Autophagy in cancer: a complex relationship. Biochem. J., 2018, 475(11), 1939-1954.
[102]
Singh, S.S.; Vats, S.; Chia, A.Y.; Tan, T.Z.; Deng, S.; Ong, M.S.; Arfuso, F.; Yap, C.T.; Goh, B.C.; Sethi, G.; Huang, R.Y.; Shen, H.M.; Manjithaya, R.; Kumar, A.P. Dual role of autophagy in hallmarks of cancer. Oncogene, 2018, 37(9), 1142-1158.
[103]
Wang, Y.; Zhang, N.; Zhang, L.; Li, R.; Fu, W.; Ma, K.; Li, X.; Wang, L.; Wang, J.; Zhang, H.; Gu, W. Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62. Mol. Cell, 2016, 63(1), 34-48.
[104]
O’Connor Mark, J. Targeting the DNA damage response in cancer. Mol. Cell, 2015, 60(4), 547-560.
[105]
Sommermann, T.G.; Mack, H.I.D.; Cahir-McFarland, E. Autophagy prolongs survival after NFκB inhibition in B-cell lymphomas. Autophagy, 2012, 8(2), 265-267.
[106]
Bouwman, P.; Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat. Rev. Cancer, 2012, 12(9), 587-598.
[107]
Galluzzi, L.; Bravo-San Pedro, J.M.; Demaria, S.; Formenti, S.C.; Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol., 2016, 14, 247.
[108]
Wei, H.; Wang, C.; Croce, C.M.; Guan, J.L. p62/SQSTM1 synergizes with autophagy for tumor growth in vivo. Genes Dev., 2014, 28(11), 1204-1216.
[109]
Wei, H.; Guan, J.L. Blocking tumor growth by targeting autophagy and SQSTM1 in vivo. Autophagy, 2015, 11(5), 854-855.
[110]
Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: An overview. Cancers , 2014, 6(3), 1769-1792.
[111]
Vilenchik, M.M.; Knudson, A.G. Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer. Proc. Natl. Acad. Sci. , 2003, 100(22), 12871-12876.
[112]
Kgatle, M.M.; Spearman, C.W.; Kalla, A.A.; Hairwadzi, H.N. DNA oncogenic virus-induced oxidative stress, genomic damage, and aberrant epigenetic alterations. Oxid. Med. Cell. Longev., 2017, 20173179421
[113]
Tubbs, A.; Nussenzweig, A. Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell, 2017, 168(4), 644-656.
[114]
Caron, P.; Choudjaye, J.; Clouaire, T.; Bugler, B.; Daburon, V.; Aguirrebengoa, M.; Mangeat, T.; Iacovoni, J.S.; Ãlvarez-Quilón, A.; Cortés-Ledesma, F.; Legube, G. Non-redundant functions of ATM and DNA-PKcs in response to DNA double-strand breaks. Cell Rep., 2016, 13(8), 1598-1609.
[115]
Chang, H.H.Y.; Pannunzio, N.R.; Adachi, N.; Lieber, M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol., 2017, 18(8), 495-506.
[116]
Daley, J.M.; Sung, P. 53BP1, BRCA1, and the Choice between Recombination and end joining at DNA double-strand breaks. Mol. Cell. Biol., 2014, 34(8), 1380-1388.
[117]
Schwertman, P.; Bekker-Jensen, S.; Mailand, N. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat. Rev. Mol. Cell Biol., 2016, 17(6), 379-394.
[118]
Arnoult, N.; Correia, A.; Ma, J.; Merlo, A.; Garcia-Gomez, S.; Maric, M.; Tognetti, M.; Benner, C.W.; Boulton, S.J.; Saghatelian, A.; Karlseder, J. Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN. Nature, 2017, 549(7673), 548-552.
[119]
Hustedt, N.; Durocher, D. The control of DNA repair by the cell cycle. Nat. Cell Biol., 2017, 19(1), 1-9.
[120]
Rimessi, A.; Previati, M.; Nigro, F.; Wieckowski, M.R.; Pinton, P. Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies. Int. J. Biochem. Cell Biol, 2016, 81((Part B)), 281-293.
[121]
Di Meo, S.; Reed, T.T.; Venditti, P.; Victor, V.M. Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell. Longev., 2016, 2016, 44.
[122]
Sallmyr, A.; Fan, J.; Rassool, F.V. Genomic instability in myeloid malignancies: Increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. Cancer Lett., 2008, 270(1), 1-9.
[123]
Stowe, D.F.; Camara, A.K.S. Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function. Antioxid. Redox Signal., 2009, 11(6), 1373-1414.
[124]
Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov., 2010, 9, 447.
[125]
Hau, P.; Tsao, S. Epstein-barr virus hijacks DNA damage response transducers to orchestrate its life cycle. Viruses, 2017, 9(11), 341.
[126]
Spriggs, C.; Laimins, L. Human papillomavirus and the DNA damage response: Exploiting host repair pathways for viral replication. Viruses, 2017, 9(8), 232.
[127]
Liang, X.; Pickering, M.T.; Cho, N-H.; Chang, H.; Volkert, M.R.; Kowalik, T.F.; Jung, J.U. Deregulation of DNA damage signal transduction by herpesvirus latency-associated M2. J. Virol., 2006, 80(12), 5862-5874.
[128]
Turnell, A.S.; Grand, R.J. DNA viruses and the cellular DNA-damage response. J. Gen. Virol., 2012, 93(10), 2076-2097.
[129]
Zitvogel, L.; Kepp, O.; Galluzzi, L.; Kroemer, G. Inflammasomes in carcinogenesis and anticancer immune responses. Nat. Immunol., 2012, 13(4), 343-351.
[130]
Samie, M.; Lim, J.; Verschueren, E.; Baughman, J.M.; Peng, I.; Wong, A.; Kwon, Y.; Senbabaoglu, Y.; Hackney, J.A.; Keir, M.; Mckenzie, B. Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling. Nat. Immunol., 2018, 19(3), 246-254.
[131]
Eliopoulos, A.G.; Havaki, S.; Gorgoulis, V.G. DNA damage response and autophagy: A meaningful partnership. Front. Genet., 2016, 7, 204.
[132]
Rodriguez-Rocha, H.; Garcia-Garcia, A.; Panayiotidis, M.I.; Franco, R. DNA damage and autophagy. Mutat. Res., 2011, 711(1–2), 158-166.
[133]
Su, M.; Mei, Y.; Sinha, S. Role of the crosstalk between autophagy and apoptosis in cancer. J. Oncol., 2013, 2013, 14.
[134]
Wang, Y. Zhu.; W.G.; Zhao, Y. Autophagy substrate SQSTM1/p62 regulates chromatin ubiquitination during the DNA damage response. Autophagy, 2017, 13(1), 212-213.
[135]
Uckelmann, M.; Sixma, T.K. Histone ubiquitination in the DNA damage response. DNA Repair , 2017, 56, 92-101.
[136]
An, L.; Jiang, Y.; Ng, H.H.W.; Man, E.P.S.; Chen, J.; Khoo, U-S.; Gong, Q.; Huen, M.S.Y. Dual-utility NLS drives RNF169-dependent DNA damage responses. Proc. Natl. Acad. Sci., 2017, 114(14), E2872-E2881.
[137]
Liu, E.Y.; Xu, N.; O’Prey, J.; Lao, L.Y.; Joshi, S.; Long, J.S.; O’Prey, M.; Croft, D.R.; Beaumatin, F.; Baudot, A.D.; Mrschtik, M. Loss of autophagy causes a synthetic lethal deficiency in DNA repair. Proc. Natl. Acad. Sci. , 2015, 112(3), 773-778.
[138]
Dellaire, G.; Bazett-Jones, D.P. PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. BioEssays, 2004, 26(9), 963-977.
[139]
Chen, S.; Wang, C.; Sun, L.; Wang, D.L.; Chen, L.; Huang, Z.; Yang, Q.; Gao, J.; Yang, X.B.; Chang, J.F.; Chen, P. RAD6 promotes homologous recombination repair by activating the autophagy-mediated degradation of heterochromatin protein HP1. Mol. Cell. Biol., 2015, 35(2), 406-416.
[140]
Park, C.; Suh, Y.; Cuervo, A.M. Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat. Commun., 2015, 6, 6823.
[141]
Deretic, V. Autophagy as an innate immunity paradigm: Expanding the scope and repertoire of pattern recognition receptors. Curr. Opin. Immunol., 2012, 24(1), 21-31.
[142]
Deretic, V.; Levine, B. Autophagy balances inflammation in innate immunity. Autophagy, 2018, 1-9.
[143]
Li, T.; Chen, Z.J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med., 2018, 215(5), 1287-1299.
[144]
Wang, L.; Ning, S. “Toll-free†pathways for production of type I interferons. AIMS Allergy Immunol, 2017, 1(3), 143-163.
[145]
Ng, K.W.; Marshall, E.A.; Bell, J.C.; Lam, W.L. cGAS–STING and cancer: Dichotomous roles in tumor immunity and development. Trends Immunol., 2018, 39, 44-54.
[146]
Konno, H.; Konno, K.; Barber Glen, N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell, 2013, 155(3), 688-698.
[147]
Liu, S.; Cai, X.; Wu, J.; Cong, Q.; Chen, X.; Li, T.; Du, F.; Ren, J.; Wu, Y.T.; Grishin, N.V.; Chen, Z.J. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science, 2015, 347(6227)aaa2630
[148]
Liang, Q.; Seo, G.J.; Choi, Y.J.; Kwak, M.J.; Ge, J.; Rodgers, M.A.; Shi, M.; Leslie, B.J.; Hopfner, K.P.; Ha, T.; Oh, B.H. Crosstalk between the cGAS DNA sensor and beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe, 2014, 15(2), 228-238.
[149]
Olagnier, D.; Brandtoft, A.M.; Gunderstofte, C.; Villadsen, N.L.; Krapp, C.; Thielke, A.L.; Laustsen, A.; Peri, S.; Hansen, A.L.; Bonefeld, L.; Thyrsted, J. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. communic, 9(1), 3506.
[150]
Sliter, D.A.; Martinez, J.; Hao, L.; Chen, X.; Sun, N.; Fischer, T.D.; Burman, J.L.; Li, Y.; Zhang, Z.; Narendra, D.P.; Cai, H. Parkin and PINK1 mitigate STING-induced inflammation. Nature, 2018, 561(7722), 258-262.
[151]
de Galarreta, M.R.; Lujambio, A. DNA sensing in senescence. Nat. Cell Biol., 2017, 19(9), 1008-1009.
[152]
Harding, S.M.; Benci, J.L.; Irianto, J.; Discher, D.E.; Minn, A.J.; Greenberg, R.A. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature, 2017, 548(7668), 466-470.
[153]
Gluck, S.; Guey, B.; Gulen, M.F.; Wolter, K.; Kang, T.W.; Schmacke, N.A.; Bridgeman, A.; Rehwinkel, J.; Zender, L.; Ablasser, A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol., 2017, 19(9), 1061.
[154]
Lee, Y.H.; Ko, J.; Joung, I.; Kim, J-H.; Shin, J. Immediate early response of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. FEBS Lett., 1998, 438(3), 297-300.
[155]
Marino, G.; Niso-Santano, M.; Baehrecke, E.H.; Kroemer, G. Self-consumption: The interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol., 2014, 15(2), 81-94.
[156]
Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol., 2007, 8(9), 741-752.
[157]
Song, S.; Tan, J.; Miao, Y.; Li, M.; Zhang, Q. Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress. J. Cell. Physiol., 2017, 232(11), 2977-2984.
[158]
Marquez, R.T.; Xu, L. Bcl-2:Beclin 1 complex: Multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am. J. Cancer Res., 2012, 2(2), 214-221.
[159]
Luo, S.; Garcia-Arencibia, M.; Zhao, R.; Puri, C.; Toh Pearl, P.C.; Sadiq, O.; Rubinsztein, D.C. Bim inhibits autophagy by recruiting beclin 1 to microtubules. Mol. Cell, 2012, 47(3), 359-370.
[160]
Pattingre, S.; Tassa, A.; Qu, X.; Garuti, R.; Liang, X.H.; Mizushima, N.; Packer, M.; Schneider, M.D.; Levine, B. Bcl-2 antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell, 2005, 122(6), 927-939.
[161]
Fernández, Ã.F.; Sebti, S.; Wei, Y.; Zou, Z.; Shi, M.; McMillan, K.L.; He, C.; Ting, T.; Liu, Y.; Chiang, W.C.; Marciano, D.K. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature, 2018, 558(7708), 136-140.
[162]
Alexander, A.; Kim, J.; Walker, C.L. ATM engages the TSC2/ mTORC1 signaling node to regulate autophagy. Autophagy, 2010, 6(5), 672-673.
[163]
Alexander, A.; Cai, S.L.; Kim, J.; Nanez, A.; Sahin, M.; MacLean, K.H.; Inoki, K.; Guan, K.L.; Shen, J.; Person, M.D.; Kusewitt, D. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl. Acad. Sci. , 2010, 107(9), 4153-4158.
[164]
Tasdemir, E.; Maiuri, M.C.; Galluzzi, L.; Vitale, I.; Djavaheri-Mergny, M.; D’amelio, M.; Criollo, A.; Morselli, E.; Zhu, C.; Harper, F.; Nannmark, U. Regulation of autophagy by cytoplasmic p53. Nat. Cell Biol., 2008, 10, 676.
[165]
Goiran, T.; Duplan, E.; Rouland, L.; el Manaa, W.; Lauritzen, I.; Dunys, J.; You, H.; Checler, F.; Alves da Costa, C. Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation. Cell Death Differ., 2018, 25(5), 873-884.
[166]
Munoz-Gamez, J.A.; Rodriguez-Vargas, J.M.; Quiles-Perez, R.; Aguilar-Quesada, R.; Martin-Oliva, D.; de Murcia, G.; Menissier de Murcia, J.; Almendros, A.; Ruiz de Almodovar, M.; Oliver, F.J. PARP-1 is involved in autophagy induced by DNA damage. Autophagy, 2009, 5(1), 61-74.
[167]
Ferguson, S.M. Beyond indigestion: Emerging roles for lysosome-based signaling in human disease. Curr. Opin. Cell Biol., 2015, 35, 59-68.
[168]
Mowers, E.E.; Sharifi, M.N.; Macleod, K.F. Autophagy in cancer metastasis. Oncogene, 2016, 36, 1619.
[169]
Levy, J.M.M.; Towers, C.G.; Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer, 2017, 17, 528.
[170]
Zhang, Y.; Mun, S.R.; Linares, J.F.; Ahn, J.; Towers, C.G.; Ji, C.H.; Fitzwalter, B.E.; Holden, M.R.; Mi, W.; Shi, X.; Moscat, J. ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nat. Commun., 2018, 9(1), 4373.