Biological consequences of structural and functional proteasome diversity

Abstract

Cell homeostasis and regulation of metabolic pathways are ensured by synthesis, proper folding and efficient degradation of a vast amount of proteins. Ubiquitin-proteasome system (UPS) degrades most intracellular proteins and thus, participates in regulation of cellular metabolism. Within the UPS, proteasomes are the elements that perform substrate cleavage. However, the proteasomes in the organism are diverse. Structurally different proteasomes are present not only in different types of cells, but also in a single cell. The reason for proteasome heterogeneity is not fully understood. This review briefly encompasses mammalian proteasome structure and function, and discusses biological relevance of proteasome diversity for a range of important cellular functions including internal and external signaling.

Keywords: Biochemistry; Cell biology; Molecular biology.

Fig. 1

Principal levels of proteasome organization. I. 20S proteasome subunit composition. Based on the composition of catalytic subunits proteasomes are divided into constitutive (2β1, 2β2, 2β5), immunoproteasomes (2β1i, 2β2i, 2β5i), intermediate proteasomes (2β1, 2β2, 2β5i), (2β1i, 2β2, 2β5i), intermediate proteasomes with assymetric subunits (for instance 2β1, 2β2, 1β5,1β5i), thymoproteasomes (2β1i, 2β2i, 2β5t). Spermatoproteasomes have unique α4s subunit. II. Binding of activator/s. Proteasomes can be found without an activator (“free”), or can carry either one or two 19S, 11Sαβ, 11Sγ and PA200 activators and likely PI31 (a proteasome inhibitor rather than activator). Hybrid proteasomes carry two different regulators. It worth mentioning that recent findings indicate preferential association of particular 20S proteasome subpopulations with particular regulators (Fabre et al., 2015). III. Post-translational modifications of proteasomes. Subunits of 20S proteasomes, as well as the regulators, can undergo different post-translational modifications including: P-phosphorylation, U-ubiquitination, S-SUMOylation, A-N-acetylation, M-myristylation, G-N-glycosylation, R-poly-ADP ribosylation, etc. (Hirano et al., 2016). For the sake of simplicity not all of the possible post-translational modifications of proteasome subunits are shown. 26S Proteasomes can associate with additional proteins that affect catalytic activity and processivity of the complex. Here PI31, Usp14, Uch37, Ube3c and Ecm29 are shown.

Fig. 2

Established and possible implications of proteasome diversity. Central column middle. Different proteasome forms degrade different proteins, produce altering sets of canonical (Guillaume et al., 2010; Kincaid et al., 2011; Mishto et al., 2014; Sasaki et al., 2015; Toes et al., 2001) and spliced peptides (Dalet et al., 2011), as well as may have varying efficacy in generation of functional cleavage products. Central column bottom. Some peptides generated by proteasomes are not processed immediately to the single amino acids and might be implicated in regulation of enzymes activity, signaling, protein targeting, protein stability, protein-protein interactions and folding (Ferro et al., 2014). Left column. Immune and intermediate proteasomes increase generation of peptides suitable for MHCI presentation, ensuring more efficient immune recognition of infected or cancer cells by circulating CD8+ T-lymphocytes. Central column top. 20S proteasome integrated into the neuronal membrane produce extracellular biologically active peptides from intracellular proteins, thus mediating communication between neurons (Ramachandran and Margolis, 2017). It was shown that some of membrane-associated 20S proteasomes contain β5i subunit, indicating at least possible presence of intermediate proteasomes. Therefore, different 20S complexes by producing altered peptide sets can mediate different signals. Right column. Proteasomes and generated peptides can also participate in long distance extracellular communication. Different forms of the proteasomes and bioactive peptides can be packed into exosomes and microvesicles along with other proteins (Bochmann et al., 2014; Lai et al., 2012). During trafficking in the exosomes, proteasomes can also cleave co-packed proteins into the biologically active peptides. Upon delivery to a target cell, the peptides and proteasomes can fulfill biological function. Extracellular vesicle (EV) cargo might be also released into the extracellular space. Thus, EVs likely represent a source of extracellular proteasomes and certain peptides. Some proteasome subpopulations and regulators are omitted on the image for the sake of simplicity. Star indicates the functional activity.