SQSTM1 binds to the KEAP1 subunit of the CRL3 ubiquitin liga...

created [InstanceEdit:9759167] Rothfels, Karen, 2021-11-29
dbId 9759168
displayName SQSTM1 binds to the KEAP1 subunit of the CRL3 ubiquitin liga...
modified [InstanceEdit:9766548] Rothfels, Karen, 2022-02-22
schemaClass Summation
text SQSTM1 binds to the KEAP1 subunit of the CRL3 ubiquitin ligase complex through the KEAP1 interacting region (KIR) located at residues 339-358 (Jain et al, 2010). Like NFE2L2, SQSTM1 has a KELCH1-domain binding STGE motif that is thought to interact with the KEAP1 complex in the 'open' conformation. Binding is enhanced by phosphorylation of the SQSTM1 STGE motif (Ichimura et al, 2013; reviewed in Baird and Yamamoto, 2020).
SQSTM1 is a transcriptional target of NFE2L2 and is upregulated in the presence of cellular stressors like reactive oxygen species (ROS) and electrophiles (reviewed in Baird and Yamamoto, 2020). Upregulation of SQSTM1 under stress conditions leads to competition between NFE2L2 and SQSTM1 for KEAP1 binding and results in stabilization of NFE2L2 protein levels. This establishes a positive feedback loop as NFE2L2 is able to translocate into the nucleus to promote expression of its target genes (Jain et al, 2010).
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). 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). Sestrin proteins may also play a role in targeting KEAP1 for SQSTM1-dependent autophagy (Bae et al, 2013; Ro et al, 2014).
Cite Us!