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.
Layfield, R, Copple, IM, Goldring, CE, Foster, BJ, Park, BK, Obeng, AD, Jenkins, RE, Kitteringham, NR, Lister, A
Yamamoto, M, Baird, L
Rojo de la Vega, M, Zhang, DD, Chapman, E, Harder, B, Wong, PK, Jiang, T
Svenning, S, Lamark, T, Johansen, T
Weihl, CC, Chou, TF, Razani, B, Pittman, SK, Lee, Y, Keith, AL
ubiquitin protein ligase activity of p-S349 SQSTM1 oligomer:KEAP1:NEDD8-CUL3:RBX1 [cytosol]
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