SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease

Abstract

Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease–related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2–related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease. Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease–related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2–related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease. Long-term alcohol consumption can lead to alcohol-associated liver disease (ALD), which is the leading cause of cirrhosis-related deaths.1Paik J.M. Golabi P. Younossi Y. Mishra A. Younossi Z.M. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD.Hepatology. 2020; 72: 1605-1616Google Scholar In line with the Global Status Report on Alcohol and Health in 2018 from World Health Organization, alcohol-attributable liver cirrhosis caused >600,000 deaths.2World Health OrganizationGlobal status report on alcohol and health 2018. World Health Organization, 2019Google Scholar The pathogenesis of ALD includes alcoholic fatty liver, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).2World Health OrganizationGlobal status report on alcohol and health 2018. World Health Organization, 2019Google Scholar, 3Bruha R. Dvorak K. Petrtyl J. Alcoholic liver disease.World J Hepatol. 2012; 4: 81Google Scholar, 4Qian H. Chao X. 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A. Y. S. T. T. H. K. The selective autophagy p62 the stress factor of Y. Y. Regulation of the by Opin Scholar, Y. S. S. J. R. T. Yang Y. T. T. T. A. K. T. H. T. K. of p62 the during selective 2013; Scholar, A. T. A. T. is a target for factor and a by and aggregates in the the of in the Williams J. B. Cui H. Ding promotes the of fibrosis and in mice with hepatic Hepatol. 2014; P. H. Ding of of and liver 2012; Y. S. A. T. K. S. J. of p62 in hepatocellular carcinoma target of 1 p62 to the of p62 and in A. Wang F. Wu T. T. A of by autophagy direct interaction and of p62 to increase the of and protein G. K. phosphorylation of selective of 1 is by and p62 which the and G. T. of 2015; and increases the of p62 to by and p62 Li J. Wang for p62 in the of under direct with p62 and p62 and Li J. Wang for p62 in the of under Scholar in a new of its and with p62 a role in selective autophagy also to the formation of stress granules and protein aggregates in the R. Dvorak K. Petrtyl J. Alcoholic liver disease.World J Hepatol. 2012; 4: 81Google Scholar p62 is a common component of many human disease–related cellular inclusion bodies, such as intracellular hyaline bodies and α1-antitrypsin aggregates in the H. A. T. G. L. K. the bodies and intracellular hyaline bodies in and A J Scholar, J.M. carcinoma with intracytoplasmic a report of Hepatol. Scholar, K. A. H. L. R. A. H. p62 a common component of in protein J Scholar as well as bodies, and aggregates in the S. Williams Ding W.-X. of in liver and Med. 2013; K. A. H. L. R. A. H. p62 a common component of in protein J Scholar Notably, inclusion bodies are also for K. A. H. L. R. A. H. p62 a common component of in protein J Scholar that can by protein aggregates can by and of the protein degradation pathways and the 2008; 4: Gao T. D. of autophagy to is for the regulation of stress and cell J 2007; Scholar the of hepatic protein aggregates as a for decreased autophagy which are protein aggregates, are in of patients with AH and in patients with alcoholic J. P. K. A. of alcoholic liver disease: Study Liver Dis. Scholar in a with AH by B. in K. P. to and Res. 2007; Scholar in and are associated with of alcoholic liver disease.World J Gastroenterol. 2014; 20: Scholar The of in is a hallmark of ALD, and to ALD of alcoholic liver disease.World J Gastroenterol. 2014; 20: M.H. G. S. for a and for fatty liver Scholar factors to to and increased formation and develop liver injury and K. P. to and Res. 2007; Y. A. J. H. P. Mallory-Denk formation and of 2014; Scholar also a role in with one that mice significantly which is due to of and of oxidative stress in S. formation of Mallory-Denk bodies and the role of metabolism and oxidative Scholar In aging mice are to formation compared with mice due to increased oxidative stress and decreased autophagy and S. J. R. T. H. Aging to liver Mallory-Denk 2012; Scholar are to the pathogenesis and of current ALD the spectrum of human ALD to the of human ALD, such as fibrosis, and accumulation of and hepatic Ding G. P. of alcoholic liver disease with clinical Scholar is to a and alcohol in which increases and hepatic in S. J. T. Y. B. L. A. R. H. Bataller R. I. A novel of acute-on-chronic alcoholic liver disease: a with human alcoholic Clin Res. 2020; Scholar The of are and p62. The of formation is of which is by R. S. P. Li phosphorylation its and hepatocyte Mallory-Denk J. 2012; P. inclusion formation and liver 2007; Scholar The increased and and protein quality in the accumulation of S. S. B. A. B. of protein quality in alcoholic hepatitis Scholar The of p62 to and which the of S. and of p62 are for Scholar p62 to a critical role in formation p62 mice and to of S. J. R. T. H. Aging to liver Mallory-Denk 2012; Scholar studies that p62 by protein and aggregates, such as S. Williams Ding W.-X. of in liver and Med. 2013; Scholar In to as a of selective autophagy, p62 also degradation by K. P. to and Res. 2007; Scholar the the formation and degradation by p62 the of in the multiple the intracytoplasmic hyaline bodies of p62 and A. J. J. K. A. P. F. R. J. with intracellular hyaline bodies a 37: Scholar A that of p62 leads to the formation of the aggregates of and p62 the in the formation of H. A. T. G. L. K. the bodies and intracellular hyaline bodies in and A J Scholar Both and in in which in approximately to of are in approximately of the H. A. T. G. L. K. the bodies and intracellular hyaline bodies in and A J J.M. carcinoma with intracytoplasmic a report of Hepatol. S. Y. T. A. Y. Y. in associated with viral hepatitis alcoholic liver J Scholar In with the of is A. J. J. K. A. P. F. R. J. with intracellular hyaline bodies a 37: Scholar are also by autophagy, and an increase in protein aggregates is as a of impaired K. P. to and Res. 2007; S. T. T. J. S. of p62 inclusion formation in 2007; Scholar and also and studies are to and to the liver injury and in and the few the of a number of the such as and a of and current on cellular and of cellular Scholar can in during stress as a to the on cell health by stress, and of is in many R. and of stress B. P. granules and 20: Scholar which are of and F. in 2014; Scholar can and a and can the as well as with

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