Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging

Abstract

Efficient proteostasis is crucial for somatic maintenance, and its decline during aging leads to cellular dysfunction and disease. Selective autophagy is a form of autophagy mediated by receptors that target specific cargoes for degradation and is an essential process to maintain proteostasis. The protein Sequestosome 1 (p62/SQSTM1) is a classical selective autophagy receptor, but it also has roles in the ubiquitin-proteasome system, cellular metabolism, signaling, and apoptosis. p62 is best known for its role in clearing protein aggregates via aggrephagy, but it has recently emerged as a receptor for other forms of selective autophagy such as mitophagy and lipophagy. Notably, p62 has context-dependent impacts on organismal aging and turnover of p62 usually reflects active proteostasis. In this review, we highlight recent advances in understanding the role of p62 in coordinating the ubiquitin-proteasome system and autophagy. We also discuss positive and negative effects of p62 on proteostatic status and their implications on aging and neurodegeneration. Finally, we relate the link between defective p62 and diseases of aging and examine the utility of targeting this multifaceted protein to achieve proteostatic benefits.

Keywords: aging; autophagy; neurodegenerative diseases; p62 (sequestosome 1(SQSTM1)); proteasome.

FIGURE 1

p62 domains, its multifaceted nature, and its impact on detriments associated with age-related degenerative diseases. (A) p62 protein consists of several well-characterized domains that interact with various proteins leading to p62’s involvement in diverse functions (see text for details). (B) p62 plays roles in various forms of selective autophagy, the UPS, programmed cell death, and signaling pathways. These functions are disrupted owing to mutations or aberrant expression/accumulation of p62 in several age-related degenerative diseases discussed in this review. AD Alzheimer’s Disease, ALS Amyotrophic Lateral Sclerosis, AMD Age-related Macular Degeneration, FTLD Frontotemporal Lobar Degeneration, HD Huntington’s Disease, NES Nuclear Export Sequence, NLS Nuclear Localization Sequence, NoLS Nucleolar Localization Sequence, PD Parkinson’s Disease.