Regulation of selective autophagy: the p62/SQSTM1 paradigm

In selective autophagy, cytoplasmic components are selected and tagged before being sequestered into an autophagosome by means of selective autophagy receptors such as p62/SQSTM1. In this review, we discuss how selective autophagy is regulated. An important level of regulation is the selection of proteins or organelles for degradation. Components selected for degradation are tagged, often with ubiquitin, to facilitate recognition by autophagy receptors. Another level of regulation is represented by the autophagy receptors themselves. For p62, its ability to co-aggregate with ubiquitinated substrates is strongly induced by post-translational modifications (PTMs). The transcription of p62 is also markedly increased during conditions in which selective autophagy substrates accumulate. For other autophagy receptors, the LC3-interacting region (LIR) motif is regulated by PTMs, inhibiting or stimulating the interaction with ATG8 family proteins. ATG8 proteins are also regulated by PTMs. Regulation of the capacity of the core autophagy machinery also affects selective autophagy. Importantly, autophagy receptors can induce local recruitment and activation of ULK1/2 and PI3KC3 complexes at the site of cargo sequestration.