ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

Tribolet, L.; Alexander, M.; Brice, A.; Jansen Van Vuren, P.; Rootes, C.; Mara, K.; McDonald, M.; Bruce, K.; Gough, T.; Shi, S.; Cowled, C.; Bean, A.; Stewart, C. R.

doi:10.1101/2020.11.13.381343

bioRxiv · 10.1101/2020.11.13.381343

ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

Tribolet, L.·Alexander, M.·Brice, A.·Jansen Van Vuren, P.·Rootes, C.·Mara, K.·McDonald, M.·Bruce, K.·Gough, T.·Shi, S.·Cowled, C.·Bean, A.·Stewart, C. R.

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Abstract

The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domain, previously C6orf106) is a recently-characterised inhibitor of the transcription regulators p300 and CREB-binding protein (CBP). Here we have utilised RNA-seq to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) infection. We find that inhibition of ILRUN expression increases cellular expression of several members of the renin-angiotensin aldosterone system (RAAS), including the SARS-CoV-2 entry receptor angiotensin converting enzyme 2 (ACE2). Furthermore, inhibition of ILRUN results in increased SARS-CoV-2 replication. These data identify ILRUN as a novel inhibitor of SARS-CoV-2 replication and represents, to our knowledge, the first report of ILRUN as a regulator of the RAAS. SIGNIFICANCE STATEMENTThere is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome-associated coronavirus (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions and the development of innovative and exciting therapeutic strategies and new knowledge and tools to better protect against the impacts of disease. The human protein-coding gene ILRUN is a recently-characterised inhibitor of the transcription regulators p300 and CREB-binding protein (CBP). Here we present the first evidence that ILRUN modulation has implications for SARS-CoV-2 infections. Virus infectivity assays confirmed that gene silencing of ILRUN had a proviral effect and increased SARS-CoV-2 replication, whilst over-expression of ILRUN inhibited SARS-CoV-2 production. Additionally, we observed that ILRUN also regulates the expression of key elements of the RAAS. These data have important implications for the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.

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Tribolet, L., Alexander, M., Brice, A., Jansen Van Vuren, P., Rootes, C., Mara, K., McDonald, M., Bruce, K., Gough, T., Shi, S., Cowled, C., Bean, A., Stewart, C. R.. 2020-11-13. ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2. https://doi.org/10.1101/2020.11.13.381343

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