Chaperone-mediated autophagy in physiological homeostasis, disease and ageing

Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has revealed an expanding range of physiological functions regulated by CMA in an organ-specific manner. CMA not only degrades damaged proteins but also targets fully functional proteins to terminate their physiological roles. Consequently, CMA dysfunction, as observed in ageing and age-related diseases, leads to cellular alterations beyond the mere accumulation of damaged proteins. We summarize recent findings linking CMA to common diseases and discuss efforts to therapeutically target CMA in these conditions.