OmniVira

TRIM21 restricts influenza A virus replication by ubiquitination-dependent degradation of M1.

Lulu Lin1,2 Xingbo Wang1 Zhen Chen3 Tingjuan Deng1 Yan Yan1 Weiren Dong1 Yu Huang3 Jiyong Zhou1,2
Affiliations 3 institutions
  1. MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China.
  2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University First Affiliated Hospital, Hangzhou, China.
  3. Institute of Animal Husbandry and Veterinary, Fujian Academy of Agricultural Sciences, Fuzhou, China.
PMID37343022 DOI10.1371/journal.ppat.1011472 Year2023 Journal PLoS pathogens PLoS Pathog Languageeng Statusepublish

Abstract

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.

Supporting text Virus Host Location
Influenza A Virus, H5N1 Subtype 300 Influenza A Virus, H7N9 Subtype 87 Influenza A Virus, H9N2 Subtype 71 Influenza in Birds 341 Influenza, Human 286 Animals 1948 Humans 1440 Mammals 92 Ubiquitination 2 Virus Replication 191

Evidence records

3 total
Experimental Infection
1 records · 1 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE7102 Pathogenicity Experiment
Key finding

Recombinant influenza A viruses carrying M1 R95K or K242R mutations showed increased replication and more severe pathogenicity compared with wild-type virus.

Virus
Influenza A virus
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

The recombinant viruses with M1 R95K or K242R mutations were resistant to TRIM21 and exhibited more robust replication and severe pathogenicity.

Method
construction of recombinant influenza A viruses | in vivo infection of mice | pathogenicity observation
Experimental system
murine infection model
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE7100 Molecular Adaptation
Key finding

Mutation R95K in the influenza A virus M1 protein confers resistance to the host factor TRIM21-mediated ubiquitination and degradation, enhancing viral replication and pathogenicity during adaptation to mammals.

Virus
Influenza A virus
Host
Not specified
Location
Not specified
Supporting text

Recombinant viruses with M1 R95K or K242R mutations were resistant to TRIM21 and exhibited more robust replication and severe pathogenicity; the TRIM21-driven R95K mutation accumulated when the virus jumped into mammals.

Genes or proteins
M1 | TRIM21
Host factors
TRIM21
Mutations
R95K | K242R
Mechanism types
replication adaptation | virulence adaptation | host-range expansion
Genomic Evolution
1 records · 1 evidence types
Evidence type Phylogenetic Evolution
1 records
OVE7103 Phylogenetic Evolution
Key finding

Phylogenetic comparison of M1 sequences from avian influenza viruses H5N1, H7N9, and H9N2 showed a progressive accumulation of the TRIM21-driven R95K mutation associated with adaptation during viral jumps into mammals.

Virus
Influenza A virus H5N1 Influenza A virus H7N9 Influenza A virus H9N2
Host
mammals Mammalia Natural host
Location
Not specified
Supporting text

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.

Genes or proteins
M1
Analysis methods
sequence analysis | phylogenetic comparison