期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 3, 页码 976-981出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1812536116
关键词
YTHDF3; interferon innate response; antiviral immunity; FOXO3
资金
- National Natural Science Foundation of China [81788101, 31390431]
- National Key Research & Development Program of China [2018YFA0507403]
- Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2016-12M-1-003]
IFN-stimulated genes (ISGs) are essential effectors of the IFN-dependent antiviral immune response. Dysregulation of ISG expression can cause dysfunctional antiviral responses and autoimmune disorders. Epitran-scriptomic regulation, such as N-6-methyladenosine (m(6)A) modification of mRNAs, plays key roles in diverse biological processes. Here, we found that the m(6)A reader YT521-B homology domain-containing family 3 (YTHDF3) suppresses ISG expression under basal conditions by promoting translation of the transcription corepressor forkhead box protein O3 (FOXO3). YTHDF3 cooperates with two cofactors, PABP1 and eIF4G2, to promote FOXO3 translation by binding to the translation initiation region of FOXO3 mRNA. Both the YTH and the P/Q/N-rich domains of YTHDF3 were required for FOXO3 RNA-binding capacity, however, METTL3-mediated m(6)A modification was not involved in the process observed. Moreover, YTHDF3(-/-) mice had increased ISG levels and were resistant to several viral infections. Our findings uncover the role of YTHDF3 as a negative regulator of antiviral immunity through the translational promotion of FOXO3 mRNA under homeostatic conditions, adding insight into the networks of RNA-binding protein-RNA interactions in homeostatically maintaining host antiviral immune function and preventing inflammatory response.
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