Endosomal microautophagy is an integrated part of the autophagic response to amino acid starvation

Abstract

Starvation is a fundamental type of stress naturally occurring in biological systems. All organisms have therefore evolved different safeguard mechanisms to cope with deficiencies in various types of nutrients. Cells, from yeast to humans, typically respond to amino acid starvation by initiating degradation of cellular components by inducing autophagy. This degradation releases metabolic building blocks to sustain essential core cellular processes. Increasing evidence indicates that starvation-induced autophagy also acts to prepare cells for prolonged starvation by degrading key regulators of different cellular processes. In a recent study, we found that within the first hours of amino acid starvation cells elicit an autophagic response causing rapid degradation of specific proteins. The response is executed independently of both MTOR and canonical macroautophagy. Based on RNAi-mediated knockdown of essential components of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery and electron microscopy we conclude that the response relies on some sort of endosomal microautophagy, hence vesicle budding into endosomes. Substantiated by the different substrates that are selectively degraded by this novel pathway we propose that the response predominantly acts to prepare cells for prolonged starvation. Intriguingly, this includes shutting down selective macroautophagy in preparation for a massive induction of bulk macroautophagy.

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

“…Consequently, CMA does not involve the formation of vesicular structures. On the other hand, in microautophagy HSPA8 targeted entities are taken up by direct membrane invagination of either lysosomes (microautophagy) or endosomes ("endosomal microautophagy") [90]. Therefore, in microautophagy cytosolic proteins are delivered to lysosomes within vesicles.…”

Decreased expression of LRA4, a key gene involved in rhamnose metabolism, caused up-regulated expression of the genes in this pathway and autophagy in Pichia pastoris

“…Autophagy is a principal catabolic pathway for degrading cellular components including organelles and dysfunctional proteins. Some nonessential cellular components can be degraded via autophagy to synthesize critical components (Devenish and Prescott 2015;Olsvik et al 2019). Autophagy occurs at low levels under normal conditions (Huang et al 2015) and increases under adverse conditions such as nutrient deficiency, hypoxia, and oxidative stress (Onodera and Ohsumi 2005;Scherz-Shouval and Elazar 2011;Shpilka et al 2015;Weidberg et al 2011).…”

Autophagy and LRRK2 in the Aging Brain

“…This constitutive physiological activity works in parallel with the UPS to implement protein quality control and maintain the integrity of cell proteome (i.e., cellular proteostasis). Recently, the involvement of autophagy in general energy homeostasis has also been proven, since autophagy can be stimulated in response to starvation-induced stress, amino acid depletion as well as cell energy needs (Puente et al, 2016;Ho et al, 2017;Olsvik et al, 2019;Sutton et al, 2019).…”

“…Instead, endosomal microautophagy occurs at the surface of late endosomes following the formation of multivesicular bodies (MVBs), that ultimately fuse with lysosomal membrane (Sahu et al, 2011;Uytterhoeven et al, 2015;Mukherjee et al, 2016;Oku et al, 2017). This process is responsible for maintaining the turnover of cellular nutrients via both a selective and hsc70-mediated mechanism or bulk degradation of proteins and organelles, such as mitochondria, peroxisomes and portions of nucleus (Olsvik et al, 2019). While microautophagy requires autophagic proteins participation, endosomal microautophagy is strongly associated with endosomal trafficking, which requires ESCRT complex that together with hsc70 mediates a more selective degradation (Sahu et al, 2011;Uytterhoeven et al, 2015;Mukherjee et al, 2016;Oku et al, 2017).…”