COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites.

Endoplasmic reticulum exit sites (ERESs) are tubular outgrowths of endoplasmic reticulum that serve as the earliest station for protein sorting and export into the secretory pathway. How these structures respond to different cellular conditions remains unclear. Here, we report that ERESs undergo lysosome-dependent microautophagy when Ca2+ is released by lysosomes in response to nutrient stressors such as mTOR inhibition or amino acid starvation in mammalian cells. Targeting and uptake of ERESs into lysosomes were observed by super-resolution live-cell imaging and focus ion beam scanning electron microscopy (FIB-SEM). The mechanism was ESCRT dependent and required ubiquitinated SEC31, ALG2, and ALIX, with a knockout of ALG2 or function-blocking mutations of ALIX preventing engulfment of ERESs by lysosomes. In vitro, reconstitution of the pathway was possible using lysosomal lipid-mimicking giant unilamellar vesicles and purified recombinant components. Together, these findings demonstrate a pathway of lysosome-dependent ERES microautophagy mediated by COPII, ALG2, and ESCRTS induced by nutrient stress. [Display omitted] • Nutrient stress induces ER exit site delivery into the lysosome • Uptake of ER exit sites into lysosomes occurs by lysosomal engulfment • ER exit site delivery into lysosomes is mediated by COPII, ALG2, and ESCRTs machinery ER exit sites are the earliest station for protein sorting and export from the ER into the secretory pathway. Liao et al. report that under nutrient stresses, ER exit sites are delivered into lysosomes using a mechanism involving COPII, ALG2, and ESCRTs. [ABSTRACT FROM AUTHOR]