Coordinate regulation of the senescent state by selective autophagy

Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes. [Display omitted] •Systematic identification of autophagy substrate proteins in cellular senescence•Selective autophagy shapes the senescent state through regulated protein stability•Selective autophagy promotes redox homeostasis, proteostasis, and inflammation•Selective autophagy networks appear to operate in vivo senescence during human OA Lee et al. present an integrative approach combining quantitative proteomics with protein stability profiling to allow for systematic identification of autophagy substrate proteins. The authors show that during cellular senescence, autophagy plays a caretaker role in the stress support network by regulating protein stability.