Sequestosome 1 (SQSTM1/p62) at the nexus of genome integrity maintenance, proteostasis regulation and organellar homeostasis

Sequestosome 1 (SQSTM1 or p62) is a multi-domain protein that functions as a scaffold for aggregating proteins into cytoplasmic inclusions and mediating their turnover via selective autophagy. However, p62 is more than an autophagy scaffold or adaptor protein; it's linked with endo/exosomal protein trafficking and the ubiquitin proteasome system and, through its interactions with many different proteins, plays important roles in regulating cell signaling events (e.g., oxidative stress response). While its core functions are linked to proteostasis maintenance, p62 is also involved in proteostasis-independent mechanisms. In this review, we highlight the well-established role of p62 in selective autophagy in mammalian cells and harmonize known and emerging p62 functions under three main themes: proteostasis regulation, genomic integrity maintenance, and organellar homeostasis. We highlight some open questions on the potentially pivotal role of p62 in bridging these themes, which we believe would herald the next decade of research involving this versatile protein.