Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy

Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in endo-lysosomal compartments. These autophagic processes share as a first step the recognition of the same five amino acid motif in substrate proteins by the hsc70 chaperone, therefore raising the possibility of a regulatory network linking the two pathways. In this work, we demonstrate the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into the late endosome. Association and dynamics of Bag6 at the late endosome membrane change during starvation which we found that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, we establish a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways and start to elucidate the molecular mechanisms that facilitate the switch between them.