Stempel, M. | Search bioRxiv

bioRxiv2023

Novel role of bone morphogenetic protein 9 (BMP9) in innate host responses to HCMV infection

Herpesviruses modulate immune control to secure lifelong infection. The diverse mechanisms Human Cytomegalovirus (HCMV) employs in this regard can reveal unanticipated aspects of cellular signalling involved in antiviral immunity. Here, we describe a novel relationship between the transforming growth factor-beta (TGF-{beta}) family cytokine bone morphogenetic protein 9 (BMP9) and HCMV infection. We identified cross-talk between BMP9-induced and type I interferon (IFN) receptor-mediated signaling, showing that BMP9 boosts the transcriptional response to and antiviral activity of IFN{beta}, and thereby enhances restriction of HCMV replication. We also show that BMP9 is secreted by human fibroblasts upon HCMV infection. However, HCMV infection impairs BMP9-induced enhancement of the response to IFN{beta}, indicating that this innate immune signalling role of BMP9 is actively targeted by HCMV. Indeed, we show that transmembrane proteins US18 and US20, which downregulate type I BMP receptors, are necessary and sufficient to cause inhibition of BMP9-mediated boosting of the antiviral response to IFN{beta}, so that HCMV lacking US18 and US20 is more sensitive to IFN{beta}. These results demonstrate that HCMV has a mutually antagonistic relationship with BMP9 and substantially extend the growing body of evidence that BMP signalling is an underappreciated modulator of innate immunity to viral infection.

immunology↗

bioRxiv2020

The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts cytomegalovirus

Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonises several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is largely unknown. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a {beta}-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, the long (ZAP-L) and short (ZAP-S), is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP decelerates the progression of HCMV infection. SLAM-sequencing revealed that ZAP restricts HCMV at early stages of infection by destabilising a distinct subset of viral transcripts with low CG content. In summary, this report provides evidence of an important antiviral role for ZAP in host defense against HCMV infection and highlights its differentiated function during DNA virus infection.

molecular biology↗