The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains; previously C6orf106) was initially identified as a proviral factor for Hendra virus infection. More recently, ILRUN was characterized to function as an inhibitor of type I interferon (IFN) and proinflammatory cytokine expression via targeting of the IFNβ-enhancosome complex and inducing the degradation of the transcriptional coactivators CREB-binding protein (CBP) and p300.
In response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, we sought to investigate the cellular pathways regulated by ILRUN in the context SARS-CoV-2 infection. Utilizing whole transcriptome sequencing (RNA-seq) we discovered that inhibition of ILRUN expression by RNA interference alters transcription profiles of numerous cellular pathways, suggestive of pleiotropic roles for ILRUN in cell biology beyond innate immunity. Notably, we observed upregulation of the SARS-CoV-2 entry receptor ACE2 and several other members of the renin-angiotensin aldosterone system (RAAS), a key pathway involved in the regulation of blood pressure and inflammation. Additionally, transcripts of the SARS-CoV-2 coreceptors TMPRSS2 and CTSL were also upregulated, and surface expression was ACE2 protein was also observed to increase in ILRUN-deficient cells using flow cytometry.
In the context of infection, inhibition of ILRUN resulted in increased SARS-CoV-2 replication at 6 and 24 h post-infection, while overexpression of ILRUN had the opposite effect, identifying ILRUN as a novel antiviral factor at the early stages of SARS-CoV-2 replication, consistent with its regulation of SARS-CoV-2 cell entry receptors. Together, these data firstly contribute to our understanding of biological pathways that regulate host factors critical to SARS-CoV-2 infection. Secondly, they identify ILRUN as a novel regulator of the RAAS, suggesting it may have a multifaceted approach to controlling inflammation through multiple cellular pathways.