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. 2025 May 27;122(21):e2504077122.
doi: 10.1073/pnas.2504077122. Epub 2025 May 21.

CD83 suppresses endogenous March-I-dependent MHC class II ubiquitination, endocytosis, and degradation

Sunil Kaul  1 , Nelson B Cole  1 , Joanna Bandola-Simon  1 , Ying Lu  1 , Elena Tondini  1 , Even Walseng  1 , Paul A Roche  1
Affiliations

CD83 suppresses endogenous March-I-dependent MHC class II ubiquitination, endocytosis, and degradation

Sunil Kaul et al. Proc Natl Acad Sci U S A. .

Abstract

MHC class II glycoproteins (MHC-II) bind peptides derived from exogenous antigens and dendritic cells (DCs) present these peptide MHC-II (pMHC-II) complexes to antigen-specific CD4 T cells during immune responses. The turnover of surface pMHC-II on antigen-presenting cells (APCs) is controlled by ubiquitin-mediated degradation of pMHC-II by the E3 ubiquitin ligase March-I. To study March-I protein expression, we have generated a mouse in which a V5 epitope-tag was knocked-in to the endogenous March-I gene, thereby allowing us to follow the fate of March-I using high-affinity anti-V5 antibodies. Quantitative analysis revealed that resting spleen DCs and B cells express only ~500 and 125 March-I molecules/cell, respectively. Endogenous March-I protein has a very short half-life in DCs and March-I mRNA, March-I protein, and MHC-II ubiquitination are rapidly terminated upon activation of both DCs and B cells. Like March-I, CD83 is a known regulator of MHC-II expression in APCs and we also show that CD83 suppresses endogenous March-I-dependent MHC-II ubiquitination, endocytosis, and degradation in mouse spleen DCs. Thus, our study reveals molecular mechanisms for both March-I- and CD83-dependent regulation of MHC-II expression in APCs.

Keywords: MHC class II; antigen presentation; ubiquitination.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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