The selective autophagy receptor SQSTM1/p62 improves lifespan and proteostasis in an evolutionarily conserved manner

Abstract

The degradation of specific cargos such as ubiquitinated protein aggregates and dysfunctional mitochondria via macroautophagy/autophagy is facilitated by SQSTM1/p62, the first described selective autophagy receptor in metazoans. While the general process of autophagy plays crucial roles during aging, it remains unclear whether and how selective autophagy mediates effects on longevity and health. Two recent studies in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster observed gene expression changes of the respective SQSTM1 orthologs in response to environmental stressors or age and showed that overexpression of SQSTM1 is sufficient to extend lifespan and improve proteostasis and mitochondrial function in an autophagy-dependent manner in these model organisms. These findings show that increased expression of the selective autophagy receptor SQSTM1 is sufficient to induce aggrephagy in C. elegans, and mitophagy in Drosophila, and demonstrate an evolutionarily conserved role for SQSTM1 in lifespan determination.

Keywords: Aging; C. elegans; Drosophila; SQST-1; SQSTM1; aggrephagy; heat shock; mitophagy; p62; proteostasis; ref(2)P; selective autophagy.

Figure 1.

Overexpression of SQST-1/ref(2)P extends lifespan in C. elegans and Drosophila via selective autophagy. Schematic overview of the findings in two recent C. elegans and Drosophila studies, in which transcriptional changes of SQSTM1 orthologs are observed upon a hormetic heat shock and age, respectively. Furthermore, overexpression of SQST-1/ref(2)P is sufficient to extend lifespan in both species in an autophagy-gene dependent manner. Thus, SQSTM1-mediated selective autophagy of protein aggregates and dysfunctional mitochondria may contribute to organismal fitness in a conserved fashion. See text for details. Ub, ubiquitin.