Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

Abstract

Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagylysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease

“…In contrast, the obtained reduction using BTZ seems to be linear to the 'on-treatment' period, as the doubled treatment duration led to a further ∼50% reduction in the lyso-Gb3 level. BTZ function could be influenced by its ability to increase autophagy [64,65] and lysosomal exocytosis [66], which could contribute to the better clearance effect in an α-Gal A independent manner. This argues for an extension of the range of applications to patients who carry variants that do not respond sufficiently to DGJ or who do not express any functional enzyme at all, for example in combination with ERT [67].…”

FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates

“…Stress-induced cellular dysfunction is often associated with the appearance of disordered and dysfunctional proteins that must be disposed of to maintain cellular viability. Stress-induced disordered proteins are tagged with ubiquitin for intracellular degradation via the proteasome system and the autophagic pathway (Lilienbaum, 2013;Ji and Kwon, 2017). To determine whether stress-induced loss of viability is associated with FAIM recruiting to ubiquitinated proteins, we again examined FAIM KO HeLa cells.…”

FAIM opposes stress-induced loss of viability and blocks the formation of protein aggregates

“…dysfunction is often associated with the appearance of disordered and dysfunctional proteins that must be disposed of to maintain cellular viability and stress-induced disordered proteins are tagged with ubiquitin for intracellular degradation via the proteasome system and the autophagic pathway 26,27 . To determine whether stress-induced loss of viability is associated with FAIM binding to ubiquitinated proteins, we again examined FAIM KO HeLa cells.…”