Getting PIKy with the lysosome membrane (again)

Much is still unknown about microautophagy and its regulators. In our recent paper, one such regulator of microautophagy, the lipid kinase PIKfyve, is described. Previously it was found that treating cells with agents like lysomotropic drugs or proton ionophores, which alter lysosomal osmotic potential and pH, leads to a form of microautophagy that selectively degrades transmembrane proteins. Induction of this type of microautophagy is linked to a lysosomal stress response that involves the targeting of macroautophagy proteins, like ATG8s, to the lysosome membrane, through a mechanism called CASM. We found that CASM-induced microautophagy turns over ATG8s and other lysosomal membrane proteins, and requires PIKfyve activity functioning downstream of ATG8 lipidation. The lysosome biogenesis transcription factor TFEB is induced in parallel to microautophagy, in a CASM-dependent, but PIKfyve-independent manner. These findings demonstrate that stressors that engage CASM cause selective turnover by microautophagy that is coordinated with lysosome biogenesis through a mechanism that is separable through PIKfyve.