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FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression.

Publication ,  Journal Article
McFadden, MJ; Sacco, MT; Murphy, KA; Park, M; Gokhale, NS; Somfleth, KY; Horner, SM
Published in: J Mol Biol
March 30, 2022

Signaling initiated by type I interferon (IFN) results in the induction of hundreds of IFN-stimulated genes (ISGs). The type I IFN response is important for antiviral restriction, but aberrant activation of this response can lead to inflammation and autoimmunity. Regulation of this response is incompletely understood. We previously reported that the mRNA modification m6A and its deposition enzymes, METTL3 and METTL14 (METTL3/14), promote the type I IFN response by directly modifying the mRNA of a subset of ISGs to enhance their translation. Here, we determined the role of the RNA demethylase fat mass and obesity-associated protein (FTO) in the type I IFN response. FTO, which can remove either m6A or cap-adjacent m6Am RNA modifications, has previously been associated with obesity and body mass index, type 2 diabetes, cardiovascular disease, and inflammation. We found that FTO suppresses the transcription of a distinct set of ISGs, including many known pro-inflammatory genes, and that this regulation requires its catalytic activity but is not through the actions of FTO on m6Am. Interestingly, depletion of FTO led to activation of the transcription factor STAT3, whose role in the type I IFN response is not well understood. This activation of STAT3 increased the expression of a subset of ISGs. Importantly, this increased ISG induction resulting from FTO depletion was partially ablated by depletion of STAT3. Together, these results reveal that FTO negatively regulates STAT3-mediated signaling that induces proinflammatory ISGs during the IFN response, highlighting an important role for FTO in suppression of inflammatory genes.

Duke Scholars

Published In

J Mol Biol

DOI

EISSN

1089-8638

Publication Date

March 30, 2022

Volume

434

Issue

6

Start / End Page

167247

Location

Netherlands

Related Subject Headings

  • STAT3 Transcription Factor
  • RNA, Messenger
  • Methyltransferases
  • Interferon Type I
  • Inflammation
  • Humans
  • Gene Expression Regulation
  • Gene Expression
  • Biochemistry & Molecular Biology
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
 

Citation

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McFadden, M. J., Sacco, M. T., Murphy, K. A., Park, M., Gokhale, N. S., Somfleth, K. Y., & Horner, S. M. (2022). FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression. J Mol Biol, 434(6), 167247. https://doi.org/10.1016/j.jmb.2021.167247
McFadden, Michael J., Matthew T. Sacco, Kristen A. Murphy, Moonhee Park, Nandan S. Gokhale, Kim Y. Somfleth, and Stacy M. Horner. “FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression.J Mol Biol 434, no. 6 (March 30, 2022): 167247. https://doi.org/10.1016/j.jmb.2021.167247.
McFadden MJ, Sacco MT, Murphy KA, Park M, Gokhale NS, Somfleth KY, et al. FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression. J Mol Biol. 2022 Mar 30;434(6):167247.
McFadden, Michael J., et al. “FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression.J Mol Biol, vol. 434, no. 6, Mar. 2022, p. 167247. Pubmed, doi:10.1016/j.jmb.2021.167247.
McFadden MJ, Sacco MT, Murphy KA, Park M, Gokhale NS, Somfleth KY, Horner SM. FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression. J Mol Biol. 2022 Mar 30;434(6):167247.
Journal cover image

Published In

J Mol Biol

DOI

EISSN

1089-8638

Publication Date

March 30, 2022

Volume

434

Issue

6

Start / End Page

167247

Location

Netherlands

Related Subject Headings

  • STAT3 Transcription Factor
  • RNA, Messenger
  • Methyltransferases
  • Interferon Type I
  • Inflammation
  • Humans
  • Gene Expression Regulation
  • Gene Expression
  • Biochemistry & Molecular Biology
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO