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 lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show 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 late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show 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. [Display omitted] •CMA and eMI activities are upregulated in response to failure of each other•A selective part of the CMA subproteome is rerouted to eMI upon CMA blockage•Bag6 is required for substrate internalization by eMI•Starvation inhibits eMI through changes in Bag6 dynamics in late endosomes Krause et al. show compensatory mechanisms between chaperone-mediated autophagy and endosomal microautophagy (eMI) facilitated by Bag6, which is required for substrate internalization by eMI. Changes in Bag6 association with late endosomes contribute to the inhibitory effect of starvation on eMI identified in this work.