RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation

Abstract Musashi RNA-binding proteins are important post-transcriptional regulators of stem cell homeostasis and are known to be involved in viral infections. However, their role in SARS-CoV-2 infection remains largely unknown. Using computational studies, in vivo RNA immunoprecipitation, and biochemical assays, here, we establish that Musashi 1 (Msi1) interacts with viral genomic RNA through direct binding to the SARS-CoV-2 3′UTR. Importantly, binding of Msi1 to the viral 3′UTR results in translational repression that could be mediated by inhibition of poly(A) binding protein. Conversely, Msi1 knockout promotes robust viral replication and increased viral protein expression. Using 2D cell cultures, stem cells, and 3D organoids, we show that depletion of Msi1 in intestinal cells augments infection. This finding explains why the human intestine serves as a reservoir for SARS-CoV-2, in which differentiated enterocytes with negligible Msi1 levels are particularly affected. Contrarily, stem cells, which are enriched for Msi1 expression, are known to be less permissive to SARS-CoV-2 infection despite expressing the entry receptors. Our findings show how translational repression of SARS-CoV-2 by stem cell RNA-binding proteins, such as Msi1, could help evade infection.