MARCH ligases in immunity

Membrane associated RING-CH (MARCH) ubiquitin ligases control the stability, trafficking and function of important immunoreceptors, including MHC molecules and costimulatory molecule CD86. Regulation of the critical antigen presenting molecule MHC II by MARCH1 and the control of MARCH1 expression by inflammatory stimuli is a key step in the function of antigen presenting cells. MHC II ubiquitination by MARCH8 and CD83 plays a critical role in T cell thymic selection. Recent studies reveal new immune functions of MARCH ligases in innate immunity, regulation of FcγR expression and Treg development. In addition, we review the importance of MARCH in immunomodulation at the host-pathogen interface. Both bacterial and viral pathogens manipulate MARCH function, while MARCH ligases act as an important host anti-viral defence mechanism. Here, we review the role of membrane-bound MARCH ligases in immune function and provide an update on new substrates and concepts. Understanding the increasingly complex roles of MARCH E3 ligases will be vital to develop therapeutic strategies for their regulation.