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.

Figure 1

Schematic domain structure of sequestosome 1 (SQSTM1/p62). The Phox and Bem1 (PB1) domain of p62, interacting with PB1-containing proteins, such as p62, neighbor of the BRCA1 gene 1 (NBR1), atypical protein kinase Cζ (aPKCζ), or mitogen-activated protein kinase kinase kinase 3 (MEKK3) to form homo-oligomers or hetero-oligomers. The ubiquitination of the PB1 domain is mediated by tripartite motif 21 (TRIM21) to inhibit the oligomerization. The ZZ-type zinc finger (ZZ) interacts with the receptor interacting protein (RIP), the tumor necrosis factor receptor–associated factor 6 (TRAF6)–binding domain (TBS) interacts with TRAF6, and PKCζ activates the p62-mediated NF-κB pathway. p62 binds to the microtubule light chain 3 (LC3) protein through the LC3-interacting region (LIR) domain to trigger selective autophagy. p62 activates the noncanonical Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid 2–related factor 2 (NRF2) pathway by interacting with KEAP1 for its degradation via the KEAP1 interacting region (KIR) domain. The ubiquitin (UB)–associated (UBA) domain on the C terminus binds to ubiquitinated proteins. Phosphorylation of Ser403 residue on the UBA domain and Ser349 residue on KIR occur in response to selective autophagy. Both the PB1 and UBA domains play an important role in p62-mediated phase separation, which is enhanced by acetylation at K420 and K435 of p62. Ac, acetylation; C, C-terminal; CDK1, cyclin-dependent kinase 1; HDAC6, deacetylase histone deacetylase 6; N, N-terminal; P, phosphorylation; Raptor, regulatory-associated protein of mechanistic target of rapamycin; TBK1, TANK-binding kinase 1.

Figure 2

Formation and degradation of sequestosome 1 (SQSTM1/p62) bodies in selective autophagy. p62 forms homo- or hetero-oligomers via its Phox and Bem1 domain. Oligomerized p62 binds to polyubiquitinated substrates or ubiquitinated (Ub) misfolded proteins via its UB-associated domain, promoting the multivalent interactions to form larger membraneless p62 bodies. During selective autophagy process, p62 in p62 bodies can further tether with microtubule light chain 3 (LC3) via its LC3-interacting region domain to promote the degradation of p62 bodies via autophagic clearance. PE, phosphatidylethanolamine.