Interfering in the USP25-SIRT1 Interaction Reduces the Onset of Cellular Senescence
Researchers here report on the development a senostatic treatment, one that reduces the pace at which cells become senescent in aged tissues. This allows the immune system to catch up on its clearance of senescent cells, and thus the overall burden of senescence is reduced over time. The big question regarding this sort of approach is whether it will still allow senescence to occur when it should occur, such as in wound healing and potentially cancerous cells. Senostatics that act through upregulated autophagy, such as rapamycin, are demonstrated to be quite safe in this regard in mice. Novel mechanisms would need the same sort of proof, but since this mechanism involves SIRT1 activity one might be optimistic that it will be beneficial.
The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function.
Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence.
Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.