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.
A genome-wide CRISPR screen identifies HuR as a regulator of apoptosis induced by dsRNA and virus
These authors contributed equally to this work.
- Award Group:
- Funder(s): National Natural Science Foundation of China
- Award Id(s): 31970887
- Funder(s):
- Award Group:
- Funder(s): Guangdong Science and Technology Department
- Award Id(s): 2018A050506029
- Funder(s):
- Award Group:
- Funder(s): Natural Science Foundation of Guangdong province
- Award Id(s): 2021A1515011491
- Funder(s):
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Huixin Gao, Yuxia Lin, Changbai Huang, Xiaobo Li, Michael S. Diamond, Chao Liu, Rong Zhang, Ping Zhang; A genome-wide CRISPR screen identifies HuR as a regulator of apoptosis induced by dsRNA and virus. J Cell Sci 2022; jcs.258855. doi: https://doi.org/10.1242/jcs.258855
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