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.

HPV16 Induces Formation of Virus-p62-PML Hybrid Bodies to Enable Infection

“…Autophagy-adaptor protein p62/SQSTM1 (SQSTM1 for sequestosome-1, hereafter p62) is one of the key factors in autophagy. This adaptor protein binds to ubiquitinated cargos and the microtubule-associated protein 1 light chain 3 (LC3) to form autophagosomes [ 22 , 23 , 24 , 25 ]. Aside from mediating autophagic degradation, p62 is also part of cellular signaling pathways affecting cell survival and oncogenesis [ 26 , 27 ].…”

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

“…The protein p62 is a specific target of the autophagy degradation. Thus, intracellular accumulation of this protein is indicative of insufficient autophagy [ 29 ]. Indeed, an increased p62 protein level was detected in Hspa4 -KO muscle despite the increase of LC3-II, suggesting a late block in autophagy occurring after autophagosome formation, and involves autophagsome/ lysosome fusion or lysosomal degradation.…”

“…P62 is an autophagy receptor of ubiquitinated proteins that interact simultaneously with LC3 and promote the degradation of ubiquitinated protein aggregates [ 29 ]. However, no significant changes in the content of ubiquitinated proteins was found between Hspa4 -KO and WT muscles [ 22 ], suggesting that Hspa4 deletion in skeletal muscle does not impair the degradation of ubiquitinated proteins, despite of the accumulation of p62.…”

The Synergetic Effect of Egyptian Portulaca oleracea L. (Purslane) and Cichorium intybus L. (Chicory) Extracts against Glucocorticoid-Induced Testicular Toxicity in Rats through Attenuation of Oxidative Reactions and Autophagy

“…The P62 protein level is usually negatively correlated with autophagic degradation. When the autophagic flux is blocked, many ubiquitinated proteins accumulate in the cells, and the level of P62 protein will increase [ 117 , 118 ].…”