Immuno- and Constitutive Proteasomes Do Not Differ in Their Abilities to Degrade Ubiquitinated Proteins

Abstract

SummaryImmunoproteasomes are alternative forms of proteasomes that have an enhanced ability to generate antigenic peptides. Recently, Seifert and colleagues reported surprising observations concerning the functions of immunoproteasomes and cellular responses to interferon-γ: (1) that immunoproteasomes degrade ubiquitinated proteins faster than the constitutive proteasomes, (2) that polyubiquitin conjugates accumulate after interferon-γ treatment but then are preferentially degraded by immunoproteasomes, and (3) that immunoproteasome deficiency causes the formation of inclusions and more severe experimental autoimmune encephalomyelitis (EAE). In contrast, we find that polyubiquitin conjugates do not transiently accumulate following IFNγ-treatment and that immunoproteasomes do not prevent the formation of intracellular inclusions or protect against EAE. Furthermore, purified 26S constitutive and immunoproteasomes bind ubiquitin conjugates similarly and degrade them at similar rates. We conclude that, although immunoproteasomes can increase the generation of peptides appropriate for MHC class I presentation, they do not degrade ubiquitinated proteins more efficiently than constitutive particles.

Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-κB activation

“…Furthermore, it has been proposed that the immunoproteasome has a higher capacity to clear ubiquitylated proteins accumulating after stimulation with IFN-␥ (Seifert et al, 2010). However, this finding too could not be reproduced by others (Nathan et al, 2013;Kincaid et al, 2012). Unlike in the previous studies, we used two different types of primary cells directly derived from knockout mice.…”

Emerging role of immunoproteasomes in pathophysiology

“…Together, these findings led this group to conclude that immunoproteasomes are more efficient at maintaining protein homeostasis than are standard proteasomes 27 . In another study, no significant differences were reported in terms of the degradation of ubiquitinated proteins by immunoproteasomes and standard proteasomes under identical experimental conditions 28 . These reports clearly suggest that substantial efforts are still needed to provide confirmatory evidence regarding the role of immunoproteasomes in the maintenance of protein homeostasis.…”

Regulation of proteasome activity in health and disease

“…A role in the clearance of oxidatively damaged proteins was proposed [58, 59], especially during inflammation [59], in the regulation of tumor development, in lipid metabolism [60] and in NFκB signaling [58]. Whether immunoproteasomes have the capacity to alter the clearance of ubiquitinated proteins after interferon-Ɣ treatment, as has been proposed earlier [59] but is currently debated [61]. …”