Abstract
Proteasomes are responsible for intracellular proteolysis and play an important role in cellular protein homeostasis. Cells of the immune system assemble a specialized form of proteasomes, known as immunoproteasomes, in which the constitutive catalytic sites are replaced for cytokine-inducible homologues. While immunoproteasomes may fulfill all standard proteasome’ functions, they seem specially adapted for a role in MHC class I antigen processing and CD8+ T-cell activation. In this way, they may contribute to CD8+ T-cell-mediated control of intracellular infections, but also to the immunopathogenesis of autoimmune diseases. Starting at the discovery of its catalytic subunits in the genome, here, we review the observations shaping our current understanding of immunoproteasome function, and the consequential novel opportunities for immune intervention.
Highlights
Immunoproteasomes—AnThe ubiquitin-proteasome system is a tightly regulated proteolytic pathway responsible for degradation of proteins that localize to the cell nucleus or cytosol
6p led to the identification of two facultative proteasome subunits/low molecular mass the contribution of immunoproteasomes to antigen processing, and their impact on the impolypeptides (LMP) 2 and 7 (Figure 3A), interspersed between the genes thought to enmunodominance hierarchy of pathogen-specific CD8+ T-cell responses. These studies have code the recently identified transporter associated with MHC class I antigen processing revealed additional roles of immunoproteasomes in immune responses as well as novel (TAP) (Figure 3B)[9]
While the proteasome as such was found peptides found in the MHC class I antigen-binding cleft that triggers CD8+ T-cell-medito play an essential role in the classical MHC class I antigen processing pathway [21–24], ated immunity, were derived from [10]. The sequences of these two low molecular mass polypeptides (LMP) the role of the inducible subunits seemed confined to the processing and presentation of a resembled known proteasome components; they were inducible by IFNγ and twosubset of antigens [26,27]. These findings evoked the question of what precise immunodimensional gel the analysis showed that complexes immunoprecipitated with anti-prological relevance immunoproteasome subunits might have
Summary
The ubiquitin-proteasome system is a tightly regulated proteolytic pathway responsible for degradation of proteins that localize to the cell nucleus or cytosol. Proteasomes were first identified in the eighties as multicatalytic proteinase complexes present in all eukaryotic cells [2–4], but in a simpler form, exist in archaea and some eubacteria [5,6] They appear as barrelshaped particles, in eukaryotes composed of four stacked rings of seven subunits each, with catalytic activity restricted to three subunits in the inner two beta-rings (β1, β2 and β5) (Figure 1). 6p led to the identification of two facultative proteasome subunits/low molecular mass polypeptides (LMP) 2 and 7 (Figure 3A), interspersed between the genes thought to encode the recently identified transporter associated with MHC class I antigen processing (TAP) (Figure 3B) [9].
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