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

MARCH2 and MARCH3 redundantly target FcγRI for K27-linked polyubiquitination and lysosomal degradation, limiting inflammatory responses in mice.

• Why it matters: Understanding how FcγRI is regulated post-translationally is crucial for insights into immune response control and inflammation-related diseases.
• What they did: The study identified MARCH2 and MARCH3 as E3 ubiquitin ligases that associate with FcγRI, mediating its K27-linked polyubiquitination at K336 and K368, leading to degradation; knockout experiments showed increased FcγRI levels and inflammatory gene transcription.
• The result: Double knockout of MARCH2/3 enhances LPS-induced gene transcription and exacerbates inflammation in mice, indicating these ligases act as host factors to restrict FcγRI-mediated inflammation and pathogenesis.