TRIM28 is a target for paramyxovirus V proteins

AbstractSUMO-modified Tripartite Motif Protein 28 (TRIM28; KAP1) plays a crucial role in repressing endogenous retroelement (ERE) transcription. We previously provided evidence that loss of SUMO-modified TRIM28 triggered by influenza A virus (IAV) infection promotes activation of host antiviral immunity via a mechanism involving derepression of EREs and production of immunostimulatory RNAs. While the IAV NS1 protein might limit consequences of such activation via its dsRNA-binding activity, we hypothesized that other human pathogenic viruses could have evolved more direct strategies to counteract this potential ERE-based defense system. Here, we reveal that V proteins from diverse paramyxoviruses, including Measles, Mumps, Parainfluenza, and Nipah/Hendra viruses, can all engage with TRIM28. Notably, the efficiency of engagement varies markedly between virus species, a phenotype that can be linked to specific residues within the C-terminal domain of V proteins. Further mapping showed that V proteins target both the TRIM28 Coiled-Coil domain and the TRIM28 PHD-Bromodomain, which contains the functionally-relevant TRIM28 SUMO-modification sites necessary for ERE repression. In this context, while paramyxovirus infection triggers canonical stress-associated phosphorylation of TRIM28, loss of SUMO-modified TRIM28 does not occur, and minimal induction of the TRIM28-dependent ERE RNA, HERVK14C, is observed. Furthermore, pre-infection with Parainfluenza virus type 2, which encodes a V protein that efficiently engages with TRIM28, limits subsequent IAV-triggered loss of SUMO-modified TRIM28 and upregulation of HERVK14C RNA. These findings dissect the interplay between paramyxoviruses and TRIM28, providing support for the concept of a TRIM28-regulated ERE-based antiviral defense system by uncovering a potential viral antagonistic measure.ImportanceHost recognition of viral nucleic acids is fundamental for stimulating antiviral immunity. To prevent aberrant immune activation, cells must precisely differentiate “non-self” from “self” nucleic acids. Endogenous retroelements (EREs), despite their self-origin, can produce immunostimulatory RNAs that blur this distinction, and may have been functionally co-opted to enhance antiviral immunity in response to some infections. Normally, ERE transcription is repressed by the host protein TRIM28, the function of which is dynamically modulated by SUMO-modification. Here, we demonstrate that paramyxoviruses engage TRIM28, maintaining it in its repressive, SUMO-modified form during infection. We propose that this virus-host interaction limits ERE activation and consequently suppresses ERE-driven immune signaling, revealing a previously unidentified mechanism of immune evasion by paramyxoviruses.