Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tripeptidyl peptidase II (TPPII) is a multifunctional cytoplasmic serine protease. The main function of TPPII is to cleave proteasome-generated peptides into tripeptides, which can then be further degraded into free amino acids. Recent evidence suggests that TPPII plays an important role in epitope generation, but the mechanisms of TPPII in MHC class I antigen presentation remain unclear. Recent research has shed new light on the mechanisms and functions of TPPII in MHC class I antigen presentation. We therefore provide an updated review of the biological characteristics of TPPII and explore its role in MHC class I antigen presentation.
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PMID:Role of tripeptidyl peptidase II in MHC class I antigen presentation: Biological characteristics, cellular crosstalk and signaling. 2782 51

The immunoproteasome (iP) has been proposed to perform specialized roles in MHC class I antigen presentation, cytokine modulation, and T cell differentiation and has emerged as a promising therapeutic target for autoimmune disorders and cancer. However, divergence in function between the iP and the constitutive proteasome (cP) has been unclear. A global peptide library-based screening strategy revealed that the proteasomes have overlapping but distinct substrate specificities. Differing iP specificity alters the quantity of production of certain MHC I epitopes but does not appear to be preferentially suited for antigen presentation. Furthermore, iP specificity was found to have likely arisen through genetic drift from the ancestral cP. Specificity differences were exploited to develop isoform-selective substrates. Cellular profiling using these substrates revealed that divergence in regulation of the iP balances its relative contribution to proteasome capacity in immune cells, resulting in selective recovery from inhibition. These findings have implications for iP-targeted therapeutic development.
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PMID:Immunoproteasome functions explained by divergence in cleavage specificity and regulation. 2918 46

The major histocompatibility complex (MHC) class I restricted pathway of antigen processing allows the presentation of intracellular antigens to cytotoxic T lymphocytes. The proteasome is the main protease in the cytoplasm and the nucleus, which is responsible for the generation of most peptide ligands of MHC-I molecules. Peptides produced by the proteasome can be further trimmed or destroyed by numerous cytosolic or endoplasmic reticulum (ER) luminal proteases. Small molecule inhibitors are useful tools for probing the role of proteases in MHC class I antigen processing. Here, we describe different methods to test the impact of protease inhibitors in antigen presentation assays.
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PMID:Testing the Impact of Protease Inhibitors in Antigen Presentation Assays. 3114 32

Classical swine fever (CSF) is a major infectious disease of pigs caused by classical swine fever virus (CSFV). NS3 is one of the non-structural proteins of CSFV and plays an important role in the infection process. However, the NS3-interacting cellular proteins involved in viral replication are poorly documented. In this study, proteasome subunit beta 10 (PSMB10) was identified as a novel NS3-interacting partner using yeast two-hybrid screening of a porcine peripheral blood mononuclear cell (PBMC) cDNA library. The PSMB10-NS3 interaction was confirmed by co-immunoprecipitation, glutathione S-transferase pulldown, and laser confocal microscopy. Overexpression of PSMB10 inhibited CSFV replication. Conversely, CSFV infection inhibited PSMB10 expression. Furthermore, we demonstrated that NS3 is degraded by PSMB10 through the ubiquitin-proteasome system and that CSFV inhibits the expression of MHC class I antigen presentation-related transporter proteins, whereas PSMB10 can restore the function of MHC class I antigen presentation and inhibit CSFV proliferation.
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PMID:Host cell protein PSMB10 interacts with viral NS3 protein and inhibits the growth of classical swine fever virus. 3149 57

MHC class I molecules on the cellular surface display peptides that either derive from endogenous proteins (self or viral), or from endocytosis of molecules, dying cells or pathogens. The conventional antigen-processing pathway for MHC class I presentation depends on proteasome-mediated degradation of the protein followed by transporter associated with antigen-processing (TAP)-mediated transport of the generated peptides into the endoplasmic reticulum (ER). Here, peptides are loaded onto MHC I molecules before transportation to the cell surface. However, several alternative mechanisms have emerged. These include TAP-independent mechanisms, the vacuolar pathway and involvement of autophagy. Autophagy is a cell intrinsic recycling system. It also functions as a defence mechanism that removes pathogens and damaged endocytic compartments from the cytosol. Therefore, it appears likely that autophagy would intersect with the MHC class I presentation pathway to alarm CD8+ T cells of an ongoing intracellular infection. However, the importance of autophagy as a source of antigen for presentation on MHC I molecules remains to be defined. Here, original research papers which suggest involvement of autophagy in MHC I antigen presentation are reviewed. The antigens are from herpesvirus, cytomegalovirus and chlamydia. The studies point towards autophagy as important in MHC class I presentation of endogenous proteins during conditions of immune evasion. Because autophagy is a regulated process which is induced upon activation of, for example, pattern recognition receptors (PRRs), it will be crucial to use relevant stimulatory conditions together with primary cells when aiming to confirm the importance of autophagy in MHC class I antigen presentation in future studies.
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PMID:Involvement of autophagy in MHC class I antigen presentation. 3296 99


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