Regulation of MHC class II and CD86 expression by March-I in immunity and disease.

The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to prevent autoimmunity. Surface expression of these proteins is regulated by their dynamic ubiquitination by the E3 ubiquitin ligase March-I. March-I promotes turnover of peptide-MHC-II complexes on resting APCs and termination of March-I expression promotes MHC-II and CD86 surface stability.

Ubiquitination of MHC Class II by March-I Regulates Dendritic Cell Fitness.

The expression and turnover of Ag-specific peptide-MHC class II (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to efficiently activate CD4 T cells. Ubiquitination of pMHC-II by the E3 ubiquitin ligase March-I regulates surface expression and survival of pMHC-II in DCs. We now show that despite their high levels of surface pMHC-II, MHC class II (MHC-II) ubiquitination-deficient mouse DCs are functionally defective; they are poor stimulators of naive CD4 T cells and secrete IL-12 in response to LPS stimulation poorly.

The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner.

Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells.

Dysfunction of antigen processing and presentation by dendritic cells in cancer.

The ability to mount an effective anti-tumor immune response requires coordinate control of CD4 T cell and CD8 T cell function by antigen presenting cells (APCs). Unfortunately, tumors create an immunosuppressive microenvironment that helps protect tumor cells from immune recognition. In many cases this defect can be traced back to a failure of APCs (most importantly dendritic cells (DCs)) to recognize, process, and present tumor antigens to T cells.

Ubiquitin-conjugating enzyme E2 D1 (Ube2D1) mediates lysine-independent ubiquitination of the E3 ubiquitin ligase March-I.

March-I is a membrane-bound E3 ubiquitin ligase belonging to the membrane-associated RING-CH (March) family. March-I ubiquitinates and down-regulates the expression of major histocompatibility complex (MHC) class II and cluster of differentiation 86 (CD86) in antigen-presenting cells. March-I expression is regulated both transcriptionally and posttranslationally, and it has been reported that March-I is ubiquitinated and that this ubiquitination contributes to March-I turnover.