Functional Differences between Proteasome Subtypes

Abstract

Four proteasome subtypes are commonly present in mammalian tissues: standard proteasomes, which contain the standard catalytic subunits β1, β2 and β5; immunoproteasomes containing the immuno-subunits β1i, β2i and β5i; and two intermediate proteasomes, containing a mix of standard and immuno-subunits. Recent studies revealed the expression of two tissue-specific proteasome subtypes in cortical thymic epithelial cells and in testes: thymoproteasomes and spermatoproteasomes. In this review, we describe the mechanisms that enable the ATP- and ubiquitin-dependent as well as the ATP- and ubiquitin-independent degradation of proteins by the proteasome. We focus on understanding the role of the different proteasome subtypes in maintaining protein homeostasis in normal physiological conditions through the ATP- and ubiquitin-dependent degradation of proteins. Additionally, we discuss the role of each proteasome subtype in the ATP- and ubiquitin-independent degradation of disordered proteins. We also discuss the role of the proteasome in the generation of peptides presented by MHC class I molecules and the implication of having different proteasome subtypes for the peptide repertoire presented at the cell surface. Finally, we discuss the role of the immunoproteasome in immune cells and its modulation as a potential therapy for autoimmune diseases.

Alteration of immunoproteasome mRNA in PBMCs of patients with Parkinson’s disease

“…An antioxidant response element (ARE) consensus sequence exists only in the upstream of the PSMB8 gene and are not present in other IP genes such as PSMB10 or PSMB9 30 . This nding can support the point that IP expression in PD can be regulated by Nrf2, which translocases and binds to the ARE sequence in oxidative stress condition 14,27 and leads to an increase of PSMB8 mRNA levels in the PBMCs of patients with PD. Regarding IP assembly, another reasonable explanation appears when PSMB8 is the rst requirement for the recruitment and assembly of PSMB9 and PSMB10, respectively 31,32 .…”

“…Regarding IP assembly, another reasonable explanation appears when PSMB8 is the rst requirement for the recruitment and assembly of PSMB9 and PSMB10, respectively 31,32 . This rule of IP assembly also presents that intermediate IP subtypes exist in some tissues 14 . In these accepted subtypes, the single intermediate IP (SIP) is only replaced by PSMB8 without PSMB9 and PSMB10 substitutions; thus, this may suggest that SIP can act as one of the main types of UPS in PD.…”

“…In these accepted subtypes, the single intermediate IP (SIP) is only replaced by PSMB8 without PSMB9 and PSMB10 substitutions; thus, this may suggest that SIP can act as one of the main types of UPS in PD. In addition, SIP often appears to be preferred as 20S or 26S form, whereas 20S is mainly responsible for degrading intrinsically disordered protein such as the native αsyn 33 , which is not degraded by 26S proteasome 14,34,35 . In addition, SIP expresses capase-like activity same as proteasomes and higher than IP; thus, this catalytic activity can cleave after acidic residues of α-Syn form α-Syn c-truncated species and demonstrated as a pathological form in all synucleinopathies [36][37][38] .…”

“…Except for conventional proteasomes presenting in most cell types in the body, the replacement of α-or βsubunits among the structure of constitutive proteasome can result in different proteasomes types, such as immunoproteasomes (IPs), some intermediate proteasomes, thymoproteasomes, and spermatoproteasomes 14 . Among these, the substitution of three β-catalytic subunits (β1, β2, or β5) leads to the formation of IPs.…”

Substrate-Specific Effects of Natural Genetic Variation on Proteasome Activity

“…Substrate protein factors such as unstructured initiation region length [45][46][47] , biases in amino acid composition [48][49][50] , where in the protein degradation is initiated 45 , and the stability of a protein's fold 48,51 can also alter how readily a specific protein is degraded by the proteasome. Moreover, the proteasome can exist in multiple configurations that can exhibit distinct preferences for individual protein substrates [52][53][54][55][56] . Thus, a systematic understanding of genetic effects on proteasome activity requires testing multiple proteasomal substrates with distinct sequence compositions.…”