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Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

Emily Yang1,2, Serina Huang3, Yasaman Jami-Alahmadi4

  • 1Molecular Biology Institute, University of California, Los Angeles, California, United States of America.

Plos Pathogens
|September 6, 2022
PubMed

Insights

Tripartite motif 25 (TRIM25) regulates diverse cellular functions by ubiquitinating key proteins. A specific mutation (R54P) helped identify novel TRIM25 substrates, revealing its broad impact on immunity and disease.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology

Background:

  • The tripartite motif (TRIM) family, particularly TRIM25, plays crucial roles in innate immunity and antiviral responses.
  • TRIM25-mediated ubiquitination is implicated in carcinogenesis and regulating viral infections.
  • The precise mechanisms by which TRIM25 controls diverse cellular processes remain incompletely understood.

Purpose of the Study:

  • To characterize a catalytically critical mutation (R54P) in TRIM25 to identify its substrates.
  • To elucidate the diverse cellular and antiviral functions mediated by TRIM25 through its identified substrates.

Main Methods:

  • Characterization of a TRIM25 R54P mutant to trap and identify interacting proteins.
  • Analysis of TRIM25 substrate interactions using the R54P mutant.
  • Assessment of TRIM25's antiviral activity against alphaviruses and the role of identified substrates.

Main Results:

  • The R54P mutation successfully trapped TRIM25 substrates involved in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation/stability (PABPC4).
  • The R54P mutation abrogated TRIM25's antiviral activity against alphaviruses, independent of the interferon response, indicating direct ubiquitination-mediated inhibition.
  • Knockdown of identified TRIM25 substrates like NME1 and PABPC4 diminished TRIM25's antiviral efficacy.

Conclusions:

  • TRIM25 utilizes a network of multiple substrates to exert its cellular and antiviral functions.
  • Understanding TRIM25's substrate interactions provides insights into its multifaceted roles in immunity, viral restriction, and potentially other cellular pathways.

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