TRIM29 inhibits PRRSV replication by targeting nsp11 for degradation Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1128/jvi.01512-25
· OA: W4416314049
Ubiquitination plays critical roles in viral infections. This study demonstrates that porcine reproductive and respiratory syndrome virus (PRRSV) endoribonuclease nsp11 undergoes K48-linked polyubiquitination specifically at the conserved catalytic residue lysine 173 (K173) during viral infection. This modification targets nsp11 for degradation via the ubiquitin-proteasome system (UPS), as evidenced by the profound stabilization of a ubiquitination-deficient K173R mutant. Remarkably, this ubiquitination mechanism targeting the endonuclease active site is evolutionarily conserved across most arteriviruses, including simian hemorrhagic fever virus and equine arteritis virus, with mouse lactate dehydrogenase-elevating virus being an exception. We further identify the host E3 ubiquitin ligase TRIM29 as a key regulator that binds PRRSV nsp11 via its coiled-coil domain and specifically promotes its K48-linked ubiquitination and subsequent proteasomal degradation. TRIM29-mediated degradation of nsp11 counteracts nsp11’s suppression of interferon (IFN-β) and interferon-stimulated gene production. Consequently, TRIM29 significantly inhibits PRRSV replication. Collectively, these findings uncover a conserved UPS-mediated regulatory mechanism targeting a critical arteriviral endonuclease and demonstrate TRIM29 as a potent host restriction factor that antagonizes PRRSV immune evasion by degrading nsp11. IMPORTANCE This study reveals that porcine reproductive and respiratory syndrome virus (PRRSV) nsp11 undergoes K48-linked polyubiquitination at catalytic residue K173, triggering ubiquitin-proteasome system (UPS)-mediated degradation, a mechanism conserved in most arteriviruses. The host E3 ligase TRIM29 binds nsp11 via its coiled-coil domain, catalyzing this ubiquitination to degrade nsp11. This counteracts nsp11’s suppression of interferon (IFN-β)/interferon-stimulated gene production and inhibits PRRSV replication. These findings identify TRIM29 as a key host restriction factor that disrupts viral immune evasion by targeting a conserved arteriviral endonuclease via the UPS.
