USP7 Deubiquitinates and Stabilizes SIRT1

The NAD⁺ -dependent protein deacetylase silent information regulator 1 (SIRT1) targets multiple proteins for deacetylation, and it has been implicated in a variety of cellular pathways and human diseases. However, it remains unclear how the abundance of SIRT1 is regulated. Here, by mass spectrometry analysis of SIRT1-containing protein complexes, we revealed that SIRT1 is physically associated with the ubiquitin-specific protease USP7. Importantly, we found that USP7 cleaves K48-linked polyubiquitin chains of SIRT1 and promotes SIRT1 stabilization. Accordingly, we demonstrated that treatment of cells with an enzymatic inhibitor of USP7 led to a decreased level of SIRT1 expression and accumulation of SIRT1 polyubiquitination. Collectively, our findings indicate that USP7 is a critical regulator of SIRT1 and provide a new pathway for the maintenance of SIRT1 abundance in cells. Anat Rec, 303:1337-1345, 2020. © 2019 American Association for Anatomy.