Regulating protein breakdown through proteasome phosphorylation

Abstract

The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. This article reviews the ability of several kinases to alter proteasome function through subunit phosphorylation. For example, PKA and DYRK2 stimulate the proteasome’s ability to degrade ubiquitinated proteins, peptides, and ATP, while one kinase, ASK1, inhibits proteasome function during apoptosis. Proteasome phosphorylation is likely to be important in regulating protein degradation because it occurs downstream of many hormones and neurotransmitters, in conditions that raise cAMP or cGMP levels, after calcium influx following synaptic depolarization, and during phases of the cell cycle. Beyond its physiological importance, pharmacological manipulation of proteasome phosphorylation has the potential to combat various diseases. Inhibitors of phosphodiesterases by activating PKA or PKG can stimulate proteasomal degradation of misfolded proteins that cause neurodegenerative or myocardial diseases and even reduce the associated pathology in mouse models. These observations are promising since in many proteotoxic diseases, aggregation-prone proteins impair proteasome function and disrupt protein homeostasis. Conversely, preventing subunit phosphorylation by DYRK2 slows cell cycle progression and tumor growth. However, further research is essential to determine how phosphorylation of different subunits by these (or other) kinases alter the properties of this complex molecular machine and thus influence protein degradation rates.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…This is accomplished by molecular machineries that identify damaged cellular constituents and move them to the lysosomes (autophagy) or proteasomes where they are degraded. The current understanding of the molecular mechanisms of autophagy and proteasomal degradation of proteins is reviewed in detail elsewhere (Galluzzi et al, 2017; Ver-Plank and Goldberg, 2017). In autophagy, cargo is enclosed within a membranous phagophore that then fuses with a lysosome and releases its contents into the acidic lysosomal lumen wherein hydrolases degrade the contents of the phagophore.…”

Dehydration‐responsive nuclear proteome landscape of chickpea (Cicer arietinum L.) reveals phosphorylation‐mediated regulation of stress response

“…For example, histones can be post‐transnationally acetylated, methylated, or phosphorylated, which can influence histone‐DNA interaction and recruitment of other nonhistone proteins (Rossetto, Avvakumov, & Côté, ). Phosphorylation is endorsed by a large number of kinases and phosphatases and affects multiple functional attributes of its targets including stability, localization, activity, interacting capability, and physiological role (VerPlank & Goldberg, ). Interplay between kinases and phosphatases mediates global regulation of cellular function (Li et al, ; Trotta, Konert, Rahikainen, Aro, & Kangasjärvi, ; Zhao et al, ).…”

Exploring the Regulation of Proteasome Function by Subunit Phosphorylation

“…Phosphorylation of 26S proteasome subunits is a newly appreciated mechanism for regulating protein degradation by the proteasome (1). Although more than 300 phosphorylation sites in proteasome subunits have been detected (2), for nearly all, the functional consequences of these modifications (if there are any) and the responsible kinases are unknown.…”

“…An important goal of future studies will be to determine the specific proteins that are degraded faster in each case, and whether the mechanism responsible for this accelerated proteolysis is solely through proteasome activation or also involves some unknown concomitant effect of the kinase on ubiquitination of certain proteins (1, 20). These kinases were shown to promote the degradation of individual cell proteins using cycloheximide to block translation and western blot to follow disappearance of the protein.…”