The immunoproteasome and viral infection: a complex regulator of inflammation

Abstract

During viral infection, proper regulation of immune responses is necessary to ensure successful viral clearance with minimal host tissue damage. Proteasomes play a crucial role in the generation of antigenic peptides for presentation on MHC class I molecules, and thus activation of CD8 T cells, as well as activation of the NF-κB pathway. A specialized type of proteasome called the immunoproteasome is constitutively expressed in hematopoietic cells and induced in non-immune cells during viral infection by interferon signaling. The immunoproteasome regulates CD8 T cell responses to many viral epitopes during infection. Accumulating evidence suggests that the immunoproteasome may also contribute to regulation of proinflammatory cytokine production, activation of the NF-κB pathway, and management of oxidative stress. Many viruses have mechanisms of interfering with immunoproteasome function, including prevention of transcriptional upregulation of immunoproteasome components as well as direct interaction of viral proteins with immunoproteasome subunits. A better understanding of the role of the immunoproteasome in different cell types, tissues, and hosts has the potential to improve vaccine design and facilitate the development of effective treatment strategies for viral infections.

Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection

“…IFN-γ is a predominant host factor involved in the induction of immunoproteasome activity (McCarthy and Weinberg, 2015). We detected increased expression of genes in the heart encoding immunoproteasome subunits (Fig.…”

“…Specifically, the actions of T cells and IFNs are intimately linked by the immunoproteasome, an inducible component of the ubiquitin proteasome system, which contributes to the degradation of misfolded and damaged proteins as well as processing of proteins to generate peptides presented by MHC class I (McCarthy and Weinberg, 2015). Stimulation by IFN-γ and other cytokines induces the replacement of constitutively active proteasome subunits (β1, β2, and β5) by immuno subunits (β1i, β2i, and β5i), and the incorporation of the proteasome activator 11S/PA28α/β, a large regulatory complex that binds the ends of the proteasome core to further enhance the ability of the proteasome to degrade short peptide substrates (Dubiel et al, 1992; Ma et al, 1992).…”

Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution

“…Nevertheless, these genes remain functionally united by their various roles within a common antigen processing and presentation pathway. Five forms of proteasome assemblies have been described in mammals: constitutive proteasome, immunoproteasome, two forms of intermediate ("mixed") proteasome, and thymoproteasome (52). The number of different proteasome compositions seems limited by constraints of cooperative subunit assembly (53) (e.g., psmb8 before psmb9), because otherwise, at least twice this number of different assemblies might be expected.…”

The Immunoproteasome in oxidative stress, aging, and disease

“…Since the mechanism by which the Immunoproteasome generates peptides for antigen presentation has been extensively reviewed (Goldberg et al, 2002, Basler et al, 2013, Angeles et al, 2012), we will not focus on that function in this review. We will also not consider the important question of infections any further, since the specific antigen can determine the response ( for a review on viral infection see (McCarthy and Weinberg, 2015)). Instead, this review will focus more on the growing recognition of the role of the Immunoproteasome in diseases and aging.…”