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. 2023 Oct 31;42(10):113192.
doi: 10.1016/j.celrep.2023.113192. Epub 2023 Sep 29.

Enzymolysis-based RNA pull-down identifies YTHDC2 as an inhibitor of antiviral innate response

Jun Zhu  1 , Shuo Liu  2 , Jiali Fang  3 , Zenghui Cui  3 , Bingjing Wang  2 , Yuzhou Wang  4 , Lin Liu  4 , Qingqing Wang  5 , Xuetao Cao  6
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Free article

Enzymolysis-based RNA pull-down identifies YTHDC2 as an inhibitor of antiviral innate response

Jun Zhu et al. Cell Rep. .
Free article

Abstract

The innate immune response must be terminated in a timely manner at the late stage of infection to prevent unwanted inflammation. The role of m6A-modified RNAs and their binding partners in this process is not well known. Here, we develop an enzymolysis-based RNA pull-down (eRP) method that utilizes the immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) to fish out m6A-modified RNA-associated proteins. We apply eRP to capture the methylated single-stranded RNA (ssRNA) probe-associated proteins and identify YT521-B homology domain-containing 2 (YTHDC2) as the m6A-modified interferon β (IFN-β) mRNA-binding protein. YTHDC2, induced in macrophages at the late stage of virus infection, recruits IFN-stimulated exonuclease ISG20 (IFN-stimulated exonuclease gene 20) to degrade IFN-β mRNA, consequently inhibiting antiviral innate immune response. In vitro and in vivo deficiency of YTHDC2 increases IFN-β production at the late stage of viral infection. Our findings establish an eRP method to effectively identify RNA-protein interactions and add mechanistic insight to the termination of innate response for maintaining homeostasis.

Keywords: CP: Immunology; RNA pull-down; RNA-binding proteins; YTHDC2; immunoglobulin G-degrading enzyme; innate immunity; mRNA degradation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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