MARCH2/3 target FcγRI for K27-linked polyubiquitination and degradation to restrict the inflammatory response

IgG Fc gamma receptor I (FcγRI) belongs to the immunoglobulin superfamily and plays a pivotal role in immune regulation. The post-translational regulation of FcγRI and its effects on immune regulation are unclear. In this study, we identified the membrane-associated RING-CH-type finger (MARCH) E3 ubiquitin ligases MARCH2 and MARCH3 as physiological regulators of FcγRI. MARCH2 and MARCH3 associate with FcγRI and mediate its K27-linked polyubiquitination at K336 and K368, respectively, leading to subsequent lysosomal degradation. While deficiency of either MARCH2 or MARCH3 modestly increases FcγRI levels as well as LPS- and IgG-induced transcription of downstream genes, double knockout of MARCH2/3 has a more dramatic effect. Double knockout of MARCH2/3 increases LPS-induced transcription of downstream genes in wild-type but not FcγRI knockout cells, and reconstitution of FcγRI^K336R/K368R into FcγRI-deficient cells increases LPS-induced transcription of the downstream genes to a higher degree than reconstitution with wild-type FcγRI. Individual knockout of MARCH2 or MARCH3 sensitizes mice to LPS-induced lung injury and Salmonella typhimurium-induced inflammation, and these effects are more severe in MARCH2/3 double-knockout mice. These findings suggest that MARCH2 and MARCH3 redundantly target FcγRI for K27-linked polyubiquitination and lysosomal degradation, thereby acting as host factors to limit the FcγRI-mediated inflammatory response and pathogenesis.