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.

Keywords: CD8; NF-κB; T cell; immunoproteasome; proteasome; viral pathogenesis.

FIGURE 1

MHC class I antigen presentation pathway. Proteins with ubiquitin tags (red spheres) are degraded by proteasomes and the resulting peptides are transported into the endoplasmic reticulum (ER) by TAP. In the ER, the peptide is loaded onto MHC class I molecules by many molecular chaperones. The peptide-MHC class I complex is then transported to the cell surface for presentation to CD8 T cells.

FIGURE 2

Immunoproteasome formation and the thymoproteasome. (A) The catalytic core of the 20S proteasome is comprised of two outer α rings and two inner β rings. IFN-γ exposure induces the synthesis of three β “immunosubunits,” which are incorporated into newly formed proteasomes in place of their constitutive counterparts to form the 20S immunoproteasome. (B) In the thymus, a specialized type of proteasome is expressed in cTECs. This proteasome contains the immunosubunits β1i and β2i as well as a cTEC-specific proteasome subunit β5t.

FIGURE 3

Possible combinations of 20S proteasome core with proteasome activator complexes. The 19S (PA700) regulatory cap can associate at one or both ends of the 20S proteasome core to form an asymmetric 26S proteasome or a 26S proteasome, respectively. The IFN-γ-induced 11S (PA28) regulatory complex can bind at the free end of a 19S-20S complex to form a hybrid proteasome, or it can associate with both ends of the 20S immunoproteasome core.