Sequestosome-1

Definition:

Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family. Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus. Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes. Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes. Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation.

References:

[1]. YouJin Lee, et al. Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell Rep. 2017 Apr 4;19(1):188-202. [Content Brief]

[2]. L Sanz, et al. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J. 1999 Jun 1;18(11):3044-53. [Content Brief]

[3]. Jiangwei Zhang, et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat Cell Biol. 2015 Oct;17(10):1259-1269. [Content Brief]

[4]. Stephan Lange, et al. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. [Content Brief]

[5]. Xuezhao Liu, et al. The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy. J Cell Biol. 2017 May 1;216(5):1301-1320. [Content Brief]

[6]. Jeganathan Ramesh Babu, et al. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem. 2005 Jul;94(1):192-203. [Content Brief]

[7]. L Sanz, et al. The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J. 2000 Apr 3;19(7):1576-86. [Content Brief]

[8]. Marlieke L M Jongsma, et al. An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport. Cell. 2016 Jun 30;166(1):152-66. [Content Brief]

[9]. Chong Teik Tan, et al. MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and suppresses Nrf2 signaling. EMBO Rep. 2021 Jan 7;22(1):e50854. [Content Brief]

[10]. Jed Long, et al. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. J Mol Biol. 2010 Feb 12;396(1):178-94. [Content Brief]

[11]. Ara Koh, et al. Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated sequestration and degradation. Cell Signal. 2014 Nov;26(11):2470-80. [Content Brief]

[12]. Emmanuel Taillebourg, et al. The deubiquitinating enzyme USP36 controls selective autophagy activation by ubiquitinated proteins. Autophagy. 2012 May 1;8(5):767-79. [Content Brief]

[13]. Thaneas Prabakaran, et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J. 2018 Apr 13;37(8):e97858. [Content Brief]

[14]. Pauline Isakson, et al. TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody ring degradation by selective autophagy. Autophagy. 2013 Dec;9(12):1955-64. [Content Brief]

[15]. M Lamar Seibenhener, et al. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004 Sep;24(18):8055-68. [Content Brief]

[16]. Eleonora Turco, et al. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat Commun. 2021 Sep 1;12(1):5212. [Content Brief]

[17]. Terje Høyvarde Clausen, et al. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy. 2010 Apr;6(3):330-44. [Content Brief]

[18]. M W Wooten, et al. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. [Content Brief]

[19]. Marie W Wooten, et al. The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem. 2005 Oct 21;280(42):35625-9. [Content Brief]

[20]. Geir Bjørkøy, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005 Nov 21;171(4):603-14. [Content Brief]

[21]. Zhiyou Wang, et al. Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity. Mol Cell Neurosci. 2005 Jun;29(2):222-31. [Content Brief]

[22]. Ashish Jain, et al. 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 Jul 16;285(29):22576-91. [Content Brief]

[23]. Thangiah Geetha, et al. 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. 2003 Feb 14;278(7):4730-9. [Content Brief]

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