Proteotoxic Stress Induces Phosphorylation of p62/SQSTM1 by ULK1 to Regulate Selective Autophagic Clearance of Protein Aggregates
Fig 9
The working model for ULK1-mediated p-S409 and p-S405 of p62 in selective degradation of ubiquitinated proteins and polyglutamine-expanded proteins.
Accumulated polyubiquitinated(poly-Ub) proteins or polyQ-expanded proteins trigger interaction of p62 with ULK1. This interaction induces ULK1-mediated p62 phosphorylation at S409 in UBA domain, which facilitates dimer to monomer transition of UBA domain, and subsequent phosphorylation at S405(mediated by either ULK1, CK2 or TBK-1). As a result, the phosphorylation of p62 at S405 and S409 leads to enhanced binding affinity of p62 to poly-Ub or polyQ-expanded proteins. The presence of ULK1 and p62 p-S405 and p-S409 in poly-Ub or polyQ-expanded protein aggregates causes the recruitment of autophagy machinery that is responsible for the degradation of poly-Ub or polyQ-Htt mutant proteins.