Structural plasticity of the proteasome and its function in antigen processing.
The proteasome is the main provider of peptide ligands for major histocompatibility complex class I molecules. During an immune response to pathogens, the proinflammatory cytokine interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha are released, which induce the proteasome subunits LMP2, LMP7, and MECL-1. These replace the constitutively expressed active site subunits of the proteasome (delta, MB1, and Z) leading to a marked change in the cleavage preference of the proteasome and the production of T-cell epitopes. Proteasome activity is further changed by the IFN-gamma-mediated induction of the proteasome regulator PA28alpha/beta and the downregulation of PA28gamma. Why such an extensive exchange of proteasome active site subunits and regulators occurs is still poorly understood. In this article we discuss recent insights in the structural consequences of proteasome reorganization and their effects on epitope generation and shaping of the cytotoxic immune response. Moreover, we review the latest data on how the ubiquitin pathway targets protein antigens for peptide processing and discuss the potential of proteasome inhibitors for the modulation of antigen presentation.
Groettrup
M
M
Research Department, Cantonal Hospital St. Gallen, Switzerland. lfal@ms1.kssg.ch
van den Broek
M
M
Schwarz
K
K
Macagno
A
A
Khan
S
S
de Giuli
R
R
Schmidtke
G
G
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex; D015398:Signal Transduction / Q000276:immunology; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology
D009097:Multienzyme Complexes; D025801:Ubiquitin; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex