Year: 2026
Type: preprint
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.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Mechanism of cell-to-cell transmission of flaviviruses, G2595216862, Reversible ADP-ribosylation signaling in the control of coronavirus infection, Discovery of Novel Mechanisms of Action of Ubiquitin-Like Proteins in Cellular Stress Pathways, Reversible ADP-ribosylation signaling in the control of coronavirus infection
OpenAlex ID: W7137975246