The Regulatory Mechanisms Governing The E3 Ubiquitin Ligase, Membrane-Associated RING-CH1 (MARCH1), And The Consequences Of Dysregulation On Metabolism

Abstract

Membrane-Associated RING-CH1 (MARCH1) is a highly-conserved E3 ubiquitin ligase identified as a potent regulator of the immune modulatory molecules, Major Histocompatibility Complex II (MHC-II), and co-stimulatory molecules (such as CD86). Antigen-presenting cells (APCs), such as dendritic cells, are induced to mature following interaction with stimuli, including microbial ligands and cytokines, whereupon MHC-II and CD86 surface expression is significantly upregulated. At the surface of the APC, these MARCH1 substrates provide signals critical for T cell activation and induction of the appropriate adaptive immune response. As a key regulator of the T cell-APC conversation, it is imperative to gain a thorough understanding of the underlying regulatory mechanisms governing MARCH1 expression and function, and the biological consequences of dysregulation of this E3 ligase. Indeed, it has been demonstrated that MARCH1 gene transcription is negatively-regulated upon APC maturation. We have shown that MARCH1 function is regulated at additional levels. We have observed that MARCH1 is rapidly degraded under normal circumstances. Further, its activity also appears to be negatively regulated by APC maturation, possibly through post-translational modifications including phosphorylation. The fact that MARCH1 is subject to multiple levels of regulation indicates a need for precise control of antigen-presentation. Interestingly, MARCH1-deficient mice on a normal diet show changes in organismal metabolism, which is known to be regulated, in part, by immune cells. We observed gender-associated dimorphisms in weight gain, visceral adipose tissue (VAT) deposits, and increased inflammation of the VAT, all characteristic of insulin-resistance and type II diabetes progression. However, despite exhibiting these hallmark risk factors of metabolic dysregulation, MARCH1-deficient mice show increased glucose tolerance compared to wildtype mice. Collectively, the data support the hypothesis that MARCH1 is stringently regulated to ensure proper control of the adaptive immune response, and suggest a novel role for this E3 ligase in the maintenance of metabolic homeostasis.