The Membrane-Associated MARCH E3 Ligase Family: Emerging Roles in Immune Regulation

Abstract

The membrane-associated RING-CH-type finger (MARCH) proteins of E3 ubiquitin ligases have emerged as critical regulators of immune responses. MARCH proteins target immune receptors, viral proteins as well as components in innate immune response for polyubiquitination and degradations via distinct routes. This review summarizes the current progress about MARCH proteins and their regulation on immune responses.

Keywords: E3 ligase; MARCH proteins; immune receptors; immune regulation; ubiquitination.

Figure 1

Structures of MARCH proteins. The domain organization for MARCH family members is shown. RING-CH, RING-CH finger domain; TM, transmembrane domain; PDZ, PDZ-binding domain; Pro rich, proline rich domain; Ser rich, serine rich domain; Tyr-based motif, tyrosine-based motif; Poly-Ser motif, poly-serine motif. The phylogenetic tree of MARCH proteins was generated with Clustal Omega alignment using the protein sequences in the Uniprot database.

Figure 2

MARCH3- and 8-mediated negative regulation of IL-1β-triggered signaling. In the early phase of IL-1β stimulation, MARCH3 is kept in inactive state by the tyrosine-protein kinase receptor TYRO3-mediated phosphorylation. In the late phase of IL-1β stimulation, MARCH3 is dephosphorylated by cell division cycle 25A (CDC25A), which in turn promotes its E3 ligase activity, leading to K48-linked polyubiquitination of IL-1 receptor type I (IL-1RI) at K409 and its lysosomal degradation. MARCH8 mediates K48-linked polyubiquitination of IL-1 receptor accessory protein (IL-1RAcP) at K512 and its proteasomal degradation upon IL-1β stimulation, leading to attenuation of IL-1β-triggered inflammatory response.