SARS-CoV-2 suppresses mRNA splicing, translation, and protein trafficking in a multipronged mechanism to evade host defenses

SARS-CoV-2 is a novel coronavirus that causes the severe respiratory disease known as COVID-19 in humans. Spread of the virus has resulted in a global pandemic and hundreds ofthousands of deaths to date. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 infection and pathogenesis. Defining the interactions betweenviral proteins and components of human cells is essential for elucidating pathogenic mechanisms and developing effective therapeutics. Here, we comprehensively define the interactions betweeneach SARS-CoV-2 protein and human RNAs. We show that 10 viral proteins form interactions at highly specific regions within several distinct RNAs including messenger RNAs and structural non-coding RNAs involved in three essential steps of proteinproduction - mRNA splicing, protein translation, and membrane and secretory protein trafficking. We show that the viral protein NSP16 binds to the mRNA recognition domains of theU1 and U2 RNA components of the spliceosome and acts to suppress global mRNA splicing in SARS-CoV-2 infected human cells. We find that NSP1 binds to a precise region on the 18Sribosomal RNA that resides in the mRNA entry channel of the initiating 40S ribosome. This interaction leads to robust, global inhibition of mRNA translation upon SARS-CoV-2 infectionof human cells. Finally, we find that NSP8 and NSP9 bind to the 7SL RNA component of the Signal Recognition Particle and interfere with protein trafficking to the cell membraneupon infection. We show that disruption of each of these essential cellular functions acts to suppress the type I interferon response to viral infection. Together, our results uncover amultipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes in order to evade host cell immune defenses.