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.
Rojo de la Vega, M,
ubiquitin protein ligase activity of p-S349 SQSTM1 oligomer:KEAP1:NEDD8-CUL3:RBX1 [cytosol]