Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy

Abstract

It is not clear to what extent starvation-induced autophagy affects the proteome on a global scale and whether it is selective. In this study, we report based on quantitative proteomics that cells during the first 4 h of acute starvation elicit lysosomal degradation of up to 2-3% of the proteome. The most significant changes are caused by an immediate autophagic response elicited by shortage of amino acids but executed independently of mechanistic target of rapamycin and macroautophagy. Intriguingly, the autophagy receptors p62/SQSTM1, NBR1, TAX1BP1, NDP52, and NCOA4 are among the most efficiently degraded substrates. Already 1 h after induction of starvation, they are rapidly degraded by a process that selectively delivers autophagy receptors to vesicles inside late endosomes/multivesicular bodies depending on the endosomal sorting complex required for transport III (ESCRT-III). Our data support a model in which amino acid deprivation elicits endocytosis of specific membrane receptors, induction of macroautophagy, and rapid degradation of autophagy receptors by endosomal microautophagy.

Exosomes: Revisiting their role as “garbage bags”

“…Moreover, in yeast and very recently in mammalian cells, it has been shown that autophagy induction is highly coordinated with protein sorting and MVE biogenesis. Autophagy receptors such as p62/SQSTM1 or NBR1 are rapidly and selectively targeted to lysosomal degradation by sorting in MVEs in starved cells, which may be a prerequisite to achieve a maximal bulk macroautophagy flux . Note that inhibition of PIKfyve activity, thus impairing MVE fusion with lysosomes, was shown to induce high enrichment of these autophagy receptors in secreted exosomes …”

“…Conversely, ESCRT components have been shown to be involved in autophagy . Moreover, in yeast and very recently in mammalian cells, it has been shown that autophagy induction is highly coordinated with protein sorting and MVE biogenesis. Autophagy receptors such as p62/SQSTM1 or NBR1 are rapidly and selectively targeted to lysosomal degradation by sorting in MVEs in starved cells, which may be a prerequisite to achieve a maximal bulk macroautophagy flux .…”

“…Autophagy receptors such as p62/SQSTM1 or NBR1 are rapidly and selectively targeted to lysosomal degradation by sorting in MVEs in starved cells, which may be a prerequisite to achieve a maximal bulk macroautophagy flux. 58 Note that inhibition of PIKfyve activity, thus impairing MVE fusion with lysosomes, was shown to induce high enrichment of these autophagy receptors in secreted exosomes. 59 MVE formation, which has until now mainly been studied regarding transmembrane protein degradation, has been found to be able to promote degradation of cytosolic components-this process is called endosomal microautophagy.…”

p62/SQSTM1: ‘Jack of all trades’ in health and cancer

“…Due to its role as a receptor for selective autophagy, p62 also localizes to cargos that will be degraded during the process, such as ubiquitin‐positive protein aggregates , damaged mitochondria, and invading bacteria . Under certain circumstances p62 can also be degraded by the proteasome or endosomal‐related autophagy , but it is primarily degraded during selective autophagy.…”

ESCRT machinery mediates selective microautophagy of endoplasmic reticulum

“…Third, it remains possible that some microautophagy pathways utilize only part of the core autophagy machinery. Importantly, ESCRT proteins are required for many types of microautophagy (Sahu et al, 2011;Liu et al, 2015;Oku et al, 2017;Tsuji et al, 2017;Mejlvang et al, 2018). While the topological equivalence of microautophagy and other ESCRT-dependent processes is compelling, a direct involvement of ESCRT machinery in microautophagy has been difficult to demonstrate.…”