UNIPROT:P62988 - FACTA Search

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Query: UNIPROT:P62988 (Ubiquitin)
4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major histocompatibility (MHC) class II molecules are cell surface glycoproteins that present extracellular antigens to CD4(+) T cells and are essential for initiation of the adaptive immune response. MHC class II expression requires recruitment of a master regulator, the class II transactivator (CIITA), to the MHC class II promoter. Post-translational modifications to CIITA play important roles in modulating CIITA mediated transcription of various genes in different cell types. We have previously linked regulation of CIITA to the Ubiquitin Proteasome System (UPS), and we and others have demonstrated that mono-ubiquitination of CIITA dramatically increases its transactivity whereas poly-ubiquitination leads to CIITA degradation. Here we identify three degron proximal lysine residues, Lys-315, Lys-330, and Lys-333, and a phosphorylation site, Ser-280, located within the CIITA degron, that regulate CIITA ubiquitination, stability, and MHC class II expression. Together, these findings contribute to the developing post-translational modification code for CIITA.
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PMID:Phosphorylation and ubiquitination of degron proximal residues are essential for class II transactivator (CIITA) transactivation and major histocompatibility class II expression. 2053 95

Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination.
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PMID:Autoregulation of MARCH1 expression by dimerization and autoubiquitination. 2250 29

MHC class II (MHC II) displays peptides at the cell surface, a process critical for CD4⁺ T cell development and priming. Ubiquitination is a mechanism that dictates surface MHC II with the attachment of a polyubiquitin chain to peptide-loaded MHC II, promoting its traffic away from the plasma membrane. In this study, we have examined how MHC II ubiquitination impacts the composition and function of both conventional CD4⁺ T cell and regulatory T cell (T_reg) compartments. Responses were examined in two models of altered MHC II ubiquitination: MHCIIKR^KI ^/KI mice that express a mutant MHC II unable to be ubiquitinated or mice that lack membrane-associated RING-CH 8 (MARCH8), the E3 ubiquitin ligase responsible for MHC II ubiquitination specifically in thymic epithelial cells. Conventional CD4⁺ T cell populations in thymus, blood, and spleen of MHCIIKR^KI/KI and March8 ^-/- mice were largely unaltered. In MLRs, March8 ^-/-, but not MHCIIKR^KI/KI, CD4⁺ T cells had reduced reactivity to both self- and allogeneic MHC II. Thymic T_reg were significantly reduced in MHCIIKR^KI/KI mice, but not March8 ^-/- mice, whereas splenic T_reg were unaffected. Neither scenario provoked autoimmunity, with no evidence of immunohistopathology and normal levels of autoantibody. In summary, MHC II ubiquitination in specific APC types does not have a major impact on the conventional CD4⁺ T cell compartment but is important for T_reg development.
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PMID:Ubiquitination of MHC Class II Is Required for Development of Regulatory but Not Conventional CD4⁺ T Cells. 3274 5