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N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections

Jian Feng, Wen Meng, Luping Chen, Xinquan Zhang, Ashley Markazi, Weiming Yuan, Yufei Huang, View ORCID ProfileShou-Jiang Gao
doi: https://doi.org/10.1101/2022.12.01.518805
Jian Feng
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Wen Meng
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Luping Chen
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Xinquan Zhang
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Ashley Markazi
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Weiming Yuan
cDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California School of Medicine, Los Angeles, CA, USA
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Yufei Huang
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
dDepartment of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, PA, USA
eDepartment of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
fDepartment of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Shou-Jiang Gao
aCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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  • ORCID record for Shou-Jiang Gao
  • For correspondence: gaos8@upmc.edu
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Abstract

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also its N6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1β, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1β, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections.

IMPORTANCE Innate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found that N6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

Footnotes

  • The authors declare no conflict of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 02, 2022.
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N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections
Jian Feng, Wen Meng, Luping Chen, Xinquan Zhang, Ashley Markazi, Weiming Yuan, Yufei Huang, Shou-Jiang Gao
bioRxiv 2022.12.01.518805; doi: https://doi.org/10.1101/2022.12.01.518805
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N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections
Jian Feng, Wen Meng, Luping Chen, Xinquan Zhang, Ashley Markazi, Weiming Yuan, Yufei Huang, Shou-Jiang Gao
bioRxiv 2022.12.01.518805; doi: https://doi.org/10.1101/2022.12.01.518805

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