J Biol Chem. 2021 Dec 14;298(1):101494. doi: 10.1016/j.jbc.2021.101494. Epub 2021 Dec 14.

Proteaphagy is specifically regulated and requires factors dispensable for general autophagy.

The Journal of biological chemistry

Kenrick A Waite, Alicia Burris, Gabrielle Vontz, Angelica Lang, Jeroen Roelofs

PMID: 34919962 PMCID: PMC8732087 DOI: 10.1016/j.jbc.2021.101494

Abstract

Changing physiological conditions can increase the need for protein degradative capacity in eukaryotic cells. Both the ubiquitin-proteasome system and autophagy contribute to protein degradation. However, these processes can be differently regulated depending on the physiological conditions. Strikingly, proteasomes themselves can be a substrate for autophagy. The signals and molecular mechanisms that govern proteasome autophagy (proteaphagy) are only partly understood. Here, we used immunoblots, native gel analyses, and fluorescent microscopy to understand the regulation of proteaphagy in response to genetic and small molecule-induced perturbations. Our data indicate that chemical inhibition of the master nutrient sensor TORC1 (inhibition of which induces general autophagy) with rapamycin induces a bi-phasic response where proteasome levels are upregulated after an autophagy-dependent reduction. Surprisingly, several conditions that result in inhibited TORC1, such as caffeinine treatment or nitrogen starvation, only induced proteaphagy (i.e., without any proteasome upregulation), suggesting a convergence of signals upstream of proteaphagy under different physiological conditions. Indeed, we found that several conditions that activated general autophagy did not induce proteaphagy, further distinguishing proteaphagy from general autophagy. Consistent with this, we show that Atg11, a selective autophagy receptor, as well as the MAP kinases Mpk1, Mkk1, and Mkk2 all play a role in autophagy of proteasomes, although they are dispensable for general autophagy. Taken together, our data provide new insights into the molecular regulation of proteaphagy by demonstrating that degradation of proteasome complexes is specifically regulated under different autophagy-inducing conditions.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: autophagy; proteaphagy; proteasome; proteasome inhibitor; protein degradation; starvation; target of rapamycin (TOR); vacuole; yeast

Conflict of interest statement

Publication Types

• Journal Article

Grant support

• P20 GM103418/GM/NIGMS NIH HHS/United States
• P20 RR017708/RR/NCRR NIH HHS/United States
• R01 GM118660/GM/NIGMS NIH HHS/United States