The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination

The ubiquitin Ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the Sirtuin family member SIRT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity. In CHIP-deficient cells, SIRT6 protein half-life is substantially reduced due to increased proteasome-mediated degradation, but CHIP overexpression in these cells increases SIRT6 protein expression without affecting SIRT6 transcription. CHIP noncanonically ubiquitinates SIRT6 at K170, which stabilizes SIRT6 and prevents SIRT6 canonical ubiquitination by other ubiquitin ligases. In CHIP-depleted cells, SIRT6 K170 mutation increases SIRT6 half-life and prevents proteasome-mediated degradation. The global decrease in SIRT6 expression in the absence of CHIP is associated with decreased SIRT6 promoter occupancy, which increases histone acetylation and promotes downstream gene transcription in CHIP-depleted cells. Cells lacking CHIP are hypersensitive to DNA-damaging agents, but DNA repair and cell viability are rescued by enforced expression of SIRT6. The discovery of this CHIP-SirT6 interaction represents a novel protein-stabilizing mechanism and defines an intersection between protein quality control and epigenetic regulation to influence pathways that regulate the biology of aging.