A genome-wide CRISPR screen identifies HuR as a regulator of apoptosis induced by dsRNA and virus

We performed an unbiased whole-genome CRISPR/Cas9 screen in A549 cells to identify potential regulators involved in cell death triggered by dsRNA. Of several top candidate genes, we identified the RNA binding protein ELAV like protein 1 (ELAVL1) that encodes Hu antigen R (HuR). Depletion of HuR led to less cell death induced by dsRNA. HuR is mainly involved in the apoptosis, and all of its RNA recognition motifs are essential for its proapoptotic function. We further showed that the HuR depletion had no influence on the mRNA level of an anti-apoptotic gene, BCL2, instead downregulated its translation in a cap-independent way. Polysome fractionation studies showed that HuR retarded the BCL2 mRNA in the non-translating pool of polysomes. Moreover, protection from dsRNA-induced apoptosis by HuR depletion required the presence of BCL2, indicating that the proapoptotic function of HuR is executed by suppressing BCL2. Consistently, HuR regulated apoptosis induced by infection of encephalomyocarditis or Semliki Forest virus. Collectively, our work identified a suite of proteins that regulate dsRNA-induced cell death, and elucidated the mechanism by which HuR acts as a pro-apoptotic factor.