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Literature detail

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.
PMID 37343022 2023 PLoS Pathog eng epublish
PubMed DOI Browse context

Article

Publication summary

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.

Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A Virus, H9N2 Subtype Influenza in Birds Influenza, Human Animals Humans Mammals Ubiquitination Virus Replication

Structured evidence records

Evidence records

2 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.80
Key finding

Comparative sequence analysis of influenza A virus M1 proteins identified an R95K mutation that accumulated during mammalian adaptation under TRIM21 selective pressure.

Virus
IAV
Host
Mammalia
Location
Not specified
Supporting text

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; comparative genomic analysis
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.98
Key finding

Influenza A viruses carrying M1 R95K or K242R mutations evade TRIM21-mediated degradation and show increased replication and pathogenicity, indicating host-driven molecular adaptation during avian-to-mammalian transmission.

Virus
IAV
Host
Not specified
Location
Not specified
Supporting text

TRIM21 binds to the residue R95 of M1 and facilitates K48 ubiquitination of M1 K242 for proteasome-dependent degradation, leading to inhibition of H3, H5, and H9 IAV replication. Recombinant viruses with M1 R95K or K242R mutations were resistant to TRIM21 and exhibited more robust replication and severe pathogenicity. Sequence analysis reveals accumulation of the TRIM21-driven R95K mutation when the virus jumps into mammals.

Genes or proteins
M1
Host factors
TRIM21
Mutations
R95K; K242R
Mechanism types
host_factor_interaction; restriction_factor_escape; pathogenicity; replication_efficiency