P62s

P62s, or p62 proteins, are a family of cytoplasmic adaptor proteins that function at the intersection of selective autophagy and intracellular signaling. The best known member is sequestosome 1 (SQSTM1/p62). P62 proteins act as autophagy receptors by binding ubiquitinated cargo through their ubiquitin-associated (UBA) domain and linking it to the autophagosomal membrane via the LC3-interacting region (LIR). Many p62 proteins also participate in signaling pathways independent of cargo degradation, making them multifunctional adaptors.

Structure is central to their function. The N-terminus contains a PB1 domain that promotes oligomerization, enabling cargo clustering. Central domains include a ZZ-type zinc finger and a TRAF6-binding (TB) region that interfaces with signaling proteins. The C-terminus houses the LIR motif for LC3 binding and the UBA domain for ubiquitin recognition. A Keap1-interacting region (KIR) mediates regulation of the Nrf2 pathway.

Functionally, p62s play a role in autophagy by tagging ubiquitinated proteins and delivering them to the autophagosome for degradation, via interaction with LC3. When autophagy is impaired, p62 accumulates and can form cytoplasmic inclusions called p62 bodies. In signaling, p62 modulates NF-κB activity and can activate the Nrf2 antioxidant response through Keap1 sequestration; it also intersects with other pathways through interactions with TRAF6 and related partners.

Clinical significance is associated with SQSTM1 mutations, which are linked to Paget’s disease of bone and have been observed in various neurodegenerative diseases and cancers. p62 accumulation serves as a marker of autophagic flux and is observed in multiple pathological conditions. Research on p62s emphasizes how oligomerization, post-translational modifications, and interactions with other autophagy receptors shape their diverse roles.

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