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TRIM21 is a molecular rheostat for influenza A virus replication
Preprint   Open access

TRIM21 is a molecular rheostat for influenza A virus replication

Qi Wen Teo, Huibin Lv, Tossapol Pholcharee, Xin Chen, Vidia Ramadin, Kevin J. Mao, Jessica J. Huang, Joel Rivera-Cardona, Jie Zhu, Yang Wei Huan, …
bioRxiv
Cold Spring Harbor Laboratory Preprints
03/17/2026
DOI: 10.64898/2026.03.16.711963
PMCID: PMC13015713
PMID: 41889827
url
https://doi.org/10.64898/2026.03.16.711963View
Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

TRIM21 is a multifunctional E3 ubiquitin ligase and intracellular antibody receptor, yet its role during viral infection remains unclear, with reports describing both antiviral and proviral activities. Here, we show that TRIM21 regulates influenza infection in an expression-dependent manner by functioning as a molecular rheostat rather than a binary restriction factor. This graded activity of TRIM21, which leads to both suppression and promotion of influenza replication, couples linkage-specific ubiquitination of viral nucleoprotein with modulation of innate immune signaling. Additionally, loss of TRIM21 unmasks a compensatory antiviral program centered on PRKDC, which is a ubiquitination target of TRIM21. This positions PRKDC as a latent restriction factor selectively engaged when primary TRIM21 control is lost. Together, these findings reveal a hierarchical and plastic antiviral network in which TRIM21 sets an adjustable threshold for host defense while restraining secondary restriction pathways. This framework highlights the sophisticated layers of regulation of the host ubiquitin-mediated antiviral immunity.

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