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ISSN 1674-7992(Online)

CN 11-5892/Q

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Front Biol    2012, Vol. 7 Issue (3) : 189-201    https://doi.org/10.1007/s11515-012-1217-z
REVIEW
Sequestosome 1/p62: a multi-domain protein with multi-faceted functions
Xiaoyan LIU, Jozsef GAL, Haining ZHU()
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
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Abstract

The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as NF-кB signaling, NRF2-driven oxidative stress response, protein turnover through the ubiquitin-proteasome pathway and the autophagosome/lysosome pathway, apoptosis and cellular metabolism. The domain structure of p62 also reflects this functional complexity since the protein appears to be a mosaic of protein interaction domains and motifs. Deregulation of the level and function of p62 and/or p62 mutations have been linked to a number of human diseases including Paget’s disease of the bone, obesity, liver diseases, tumorigenesis and neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease. In this article, we review the current understanding of the involvement of p62 in cellular processes under physiologic and pathological conditions.
Keywords sequestosome 1/p62      autophagy      ubiquitin-proteasome system      NF-κB signaling      Paget′s disease of bone      amyotrophic lateral sclerosis     
Corresponding Author(s): ZHU Haining,Email:haining@uky.edu   
Issue Date: 01 June 2012
 Cite this article:   
Jozsef GAL,Haining ZHU,Xiaoyan LIU. Sequestosome 1/p62: a multi-domain protein with multi-faceted functions[J]. Front Biol, 2012, 7(3): 189-201.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1217-z
https://academic.hep.com.cn/fib/EN/Y2012/V7/I3/189
Fig.1  The domain structure of p62. The PB1, ZZ-type zinc finger, SMIR, TB, LIR and UBA domains and the responding molecules interacting with these domains are illustrated.
Fig.2  The role of p62 as a substrate receptor in protein turnover. The p62 protein targets substrates both to the ubiquitin-proteasome system and the autophagy-lysosome pathway. Misfolded proteins are recognized by p62 by ubiquitin-dependent or-independent mechanisms. The UBA domain is critical for the ubiquitin-dependent recognition of substrates. The SMIR motif is responsible for recognizing proteins such as familial ALS-related SOD1 mutants in an ubiquitin-independent manner. The LC3 interaction region (LIR) is necessary for targeting the substrates to autophagy.
Fig.3  The role of p62 in the TNFα- and RANKL-induced NF-κB signaling pathways. The binding of TNFα to the TNF receptor induces the recruitment of TRADD to the receptor, which in turn recruits TRAF2 and RIP1. RIP1 recruits p62 and activates the phosphorylation of the IKK complex by aPKC. The binding of RANKL to RANK leads to the recruitment of TRAF6 which in turn recruits p62 and activates the aPKC-dependent phosphorylation of IKK and subsequent NF-κB nuclear translocation and activation. It is noted that polyubiquitinated RIP1 and TRAF6 can both activate the IKK complex through a p62 independent pathway involving the TAB/TAK1 complex.
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