Abstract
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.
Highlights
Introduction and Michael BaslerThe ubiquitin-proteasome system (UPS) is a multicomponent, multiprotein structure that catalyzes the proteolysis of unwanted, misfolded, and foreign proteins that have been covalently modified with ubiquitin molecules [1]
For some antigenic peptides, CD8 T cell epitopes can be processed through the constitutive proteasome and induce stronger cytotoxic responses than peptides generated by immunoproteasome subunits [39,82,83]
The immunoproteasome itself has diverse functions with outputs in a wide range of cellular processes. These effects may explain why immunoproteasome induction and inhibition have contradictory roles in different cancers, which mirrors the context-dependent role of inflammation in cancer
Summary
The ubiquitin-proteasome system (UPS) is a multicomponent, multiprotein structure that catalyzes the proteolysis of unwanted, misfolded, and foreign proteins that have been covalently modified with ubiquitin molecules [1]. The immunoproteasome carries out proteasomal degradation of protein substrates for the MHC class I restricted antigen processing pathway [7,8]. This difference in substrate specificity may impact the immunopeptidome by altering the quantity of certain epitopes This appears to be only partly explained by the increased preference of the immunoproteasome for specific P1 residues and cleavage following bulky hydrophobic amino acid residues [15]. Both proteasome isoforms have a different production kinetics affecting quantity of epitopes [16]. EMT: epithelial to mesenchymal transition, IP: immunoproteasome, CTL: cytotoxic T lymphocytes
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