TRIM21 restricts the replication of various influenza A virus subtypes by binding to the R95 residue of the M1 protein and facilitating its K48-linked ubiquitination and proteasome-dependent degradation.
TRIM21 acts as a host restriction factor against specific influenza A virus subtypes by targeting the M1 protein for degradation, which drives viral adaptive mutations in mammals.
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase, plays a critical role in the host antiviral response. However, the mechanism and antiviral spectrum of TRIM21 in influenza A virus (IAV) remain unclear. Here, we report that TRIM21 inhibits the replication of various IAV subtypes by targeting matrix protein 1 (M1) from H3/H5/H9, but not H1 and H7 M1. Mechanistically, TRIM21 binds to the residue R95 of M1 and facilitates K48 ubiquitination of M1 K242 for proteasome-dependent degradation, leading to the inhibition of H3, H5, and H9 IAV replication. Interestingly, the recombinant viruses with M1 R95K or K242R mutations were resistance to TRIM21 and exhibited more robust replication and severe pathogenicity. Moreover, the amino acid sequence M1 proteins, mainly from avian influenza such as H5N1, H7N9, H9N2, ranging from 1918 to 2022, reveals a gradual dominant accumulation of the TRIM21-driven R95K mutation when the virus jumps into mammals. Thus, TRIM21 in mammals' functions as a host restriction factor and drives a host adaptive mutation of influenza A virus.
Lin et al. (2023) studied Influenza A virus infection. TRIM21 vs. Control (TRIM21 knockout or wild-type virus) was evaluated on Viral replication and M1 protein degradation. TRIM21 restricts the replication of various influenza A virus subtypes by binding to the R95 residue of the M1 protein and facilitating its K48-linked ubiquitination and proteasome-dependent degradation.