Regulation of Proteasome Activity by (Post-)transcriptional Mechanisms

Abstract

Intracellular protein synthesis, folding, and degradation are tightly controlled processes to ensure proper protein homeostasis. The proteasome is responsible for the degradation of the majority of intracellular proteins, which are often targeted for degradation via polyubiquitination. However, the degradation rate of proteins is also affected by the capacity of proteasomes to recognize and degrade these substrate proteins. This capacity is regulated by a variety of proteasome modulations including (1) changes in complex composition, (2) post-translational modifications, and (3) altered transcription of proteasomal subunits and activators. Various diseases are linked to proteasome modulation and altered proteasome function. A better understanding of these modulations may offer new perspectives for therapeutic intervention. Here we present an overview of these three proteasome modulating mechanisms to give better insight into the diversity of proteasomes.

The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 β

“…Finally, it is plausible that proteasome activity in A20 cells is additionally modified by e.g. post-translational modifications or altered transcription of proteasomal activators, as reviewed in [57].…”

Redox Post-translational Modifications of Protein Thiols in Brain Aging and Neurodegenerative Conditions—Focus on S-Nitrosation

“…complexes I, II, IV, and V, and ATP synthase (Hurd et al, 2008;Garcia et al, 2010;Handy and Loscalzo, 2012;Wang et al, 2013;Mailloux et al, 2014;Nakamura and Lipton, 2017;van der Reest et al, 2018;Xiao et al, 2020), enzymes of the tricarboxylic acid cycle (e.g., Alpha-ketoglutarate dehydrogenase, Isocitrate dehydrogenase, Aconitase; Kil and Park, 2005;McLain et al, 2013;Yan et al, 2013;Bulteau et al, 2017;Lipton, 2017, 2020;Xiao et al, 2020), enzymes of glycolysis [e.g., Hexokinase, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH); Riederer et al, 2009;Mailloux et al, 2014;McDonagh et al, 2014;Araki et al, 2016;van der Reest et al, 2018;Xiao et al, 2020] and of fatty acid metabolism (e.g., Very long chain acyl-coenzyme A dehydrogenase; Doulias et al, 2013). Similarly, for proteostasis, redox PTMs have been reported on chaperones (e.g., Heat shock protein 70, PDI; Grunwald et al, 2014), subunits of the proteasome (Aiken et al, 2011;Jung et al, 2014;Kors et al, 2019), and proteins involved in autophagy (e.g., Autophagy Related 3, 4 and 7; Frudd et al, 2018;Pajares et al, 2018;Scherz-Shouval et al, 2019), which ultimately contribute to the regulation of protein folding and degradation (Niforou et al, 2014;Pajares et al, 2015). Redox PTMs can also regulate the activity of several transcription factors (Brigelius-Flohé and Flohé, 2011).…”

Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

“…Phosphorylation of Rpn2 at threonine 273 by p38 MAPK suppresses proteasome function (Lee et al, 2010). It has been speculated that this phosphorylation of Rpn2 causes a conformational change, affecting the accessibility of substrates to the 20S core (Kors et al, 2019). Lee et al (2010) reported purified 26S proteasomes from HeLa cells expressing activated p38 MAPK, had reduced proteolytic activities.…”