# SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation

## TL;DR

This study shows that the protein p62 helps control skin aging by breaking down USP7, and its reduced levels are linked to faster aging and cellular senescence.

## Contribution

The study reveals a novel molecular mechanism by which p62 regulates skin aging through specific interactions with USP7.

## Key findings

- p62 expression is reduced in aging skin and senescent cells, correlating with accelerated aging.
- p62 inhibits USP7 accumulation during senescence by promoting its degradation through direct binding.
- Specific amino acid residues in p62 and USP7 are critical for their interaction and regulation of aging.

## Abstract

Skin aging is a complex process driven by intrinsic genetic factors and extrinsic environmental influences. In this study, sequestosome1 (SQSTM1/p62) was identified as a key regulator of senescence, the senescence‐associated secretory phenotype (SASP), and skin aging. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of ubiquitin‐specific protease 7 (USP7) during senescence induction by orchestrating its degradation through specific binding interactions. In particular, the Tyr‐67 residue within the PB1 domain or Gln‐418 within the UBA domain of p62 forms a hydrogen bond with Ala‐993 in the Ubl5 domain of USP7. Mutations in either Tyr‐67 or Gln‐418 of p62, or Ala‐993 of USP7, resulted in the induction of cellular senescence, highlighting the critical role of these molecular interactions in the regulation of aging processes.

p62 exhibits diminished expression in aging skin and senescent cells. p62 serves to inhibit the accumulation of USP7 during senescence induction. The Tyr‐67 residue within the PB1 domain or Gln‐418 within the UBA domain of p62 forms a hydrogen bond with Ala‐993 of the Ubl5 domain of USP7.