KEAP1:CUL3:RBX1 ubiquitinates p-S349 SQSTM1 oligomer

Stable Identifier
Reaction [transition]
Homo sapiens
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SQSTM1 is an adaptor protein that mediates aggregation of target proteins for selective autophagy (reviewed in Lamark et al, 2017). SQSTM1 also intersects with the KEAP1:NFE2L2 pathway, as it is both a transcriptional target of NFE2L2 and a regulator of KEAP1. SQSTM1 has also been shown to be a substrate for KEAP1:CUL3:RBX1-mediated ubiquitination: ubiquitination at lysine 420 increases the ability of SQSTM1 to sequester and degrade target ubiquitinated proteins through selective autophagy (Lee et al, 2017; reviewed in Baird and Yamamoto, 2020; Lamark et al, 2017). Some evidence shows that in addition to competing with NFE2L2 for KEAP1-binding, SQSTM1 also targets KEAP1 for sequestration and degradation through the autophagy pathway (Copple et al, 2010; reviewed in Jiang et al, 2015). Although in this pathway, ubiqutination at K420 is shown after phosphorylation of SQSTM1 at S349, the order and mutual dependence of these two post-translational modifications has not been determined.
Literature References
PubMed ID Title Journal Year
20378532 Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway

Layfield, R, Copple, IM, Goldring, CE, Foster, BJ, Park, BK, Obeng, AD, Jenkins, RE, Kitteringham, NR, Lister, A

J Biol Chem 2010
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
26117325 p62 links autophagy and Nrf2 signaling

Rojo de la Vega, M, Zhang, DD, Chapman, E, Harder, B, Wong, PK, Jiang, T

Free Radic Biol Med 2015
29233872 Regulation of selective autophagy: the p62/SQSTM1 paradigm

Svenning, S, Lamark, T, Johansen, T

Essays Biochem 2017
28380357 Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

Weihl, CC, Chou, TF, Razani, B, Pittman, SK, Lee, Y, Keith, AL

Cell Rep 2017
Catalyst Activity

ubiquitin protein ligase activity of p-S349 SQSTM1 oligomer:KEAP1:NEDD8-CUL3:RBX1 [cytosol]

Orthologous Events
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