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Defining the role of the RNA modification N6-methyladenosine during Flaviviridae virus infection

Award Number: R01AI125416
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT RNA modifications play diverse roles in regulating viral infection. The RNA modification N6-methyladenosine (m6A) regulates infection by the positive-strand RNA viruses in the Flaviviridae family, through its effect on both viral and cellular RNA. m6A regulates key aspects of RNA biology, including RNA stability, translation, and localization, as well as interactions with m6A-binding proteins. While the basic proteins that add or bind m6A on mRNA are known, little is known about how the m6A-methyltransferase complex or m6A-binding proteins are specifically regulated or targeted to viral and cellular RNA during infection. Our previous work has revealed that the RNA genomes of viruses in the Flaviviridae family are m6A-modified at specific sites, and that m6A at one site in the hepatitis C virus (HCV) genome negatively regulates infectious particle production by inhibiting interaction of the HCV RNA genome with the viral packaging protein. We also found that Flaviviridae-induced cellular signaling pathways alter m6A changes in host mRNAs important for infection. Finally, our preliminary data identify novel m6A-methyltransferase interacting proteins and a novel m6A-reader with a described role in the antiviral interferon (IFN) response. The goal of this proposal is to elucidate the molecular mechanisms of how m6A-targeting to viral and cellular RNA regulates infection by specific viruses in the Flaviviridae family. Based on our preliminary data, the central hypothesis of this proposal is that the specific m6A regulatory pathways co-opted and induced by viral infection can be determinants of viral replication. Guided by our preliminary data, this hypothesis will be tested by pursuing the following three specific aims: 1) Define how the m6A- methyltransferase complex targets HCV RNA to regulate infection; 2) Determine how Flaviviridae infection alters m6A regulation of specific host mRNAs; 3) Characterize an IFN-induced m6A-reader that restricts Flaviviridae infection. In Aim 1, we will define how the nuclear m6A-methyltransferase is recruited to the cytoplasmic-localized RNA genome of HCV. In Aim 2, we will investigate how the m6A-methyltransferase complex is functionalized during viral infection to differentially target cellular mRNAs for methylation. In Aim 3, we will define the molecular determinants of how an IFN-induced m6A reader targets viral and host m6A-modified RNA to inhibit Flaviviridae infection. The proposed work will be significant and innovative because it will define cellular pathways and mechanisms that alter m6A-methyltransferase composition and function during Flaviviridae infection, as well as define new IFN-induced regulators of m6A, thus uncovering new host pathways exploited by viruses or utilized by the host to inhibit infection. Importantly, this work will also reveal novel aspects of how gene expression is regulated by m6A, including the fact that specific cellular signaling pathways alter how m6A is placed on specific mRNAs. Thus, this work has broad implications for understanding a host of human diseases that are caused by altered gene expression and regulated by RNA modifications.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $541,455 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	8	1/17/2024	NON-COMPETING CONTINUATION	$541,455
														Subtotal = $541,455

Issue Date FY: 2023 ( Subtotal = $601,533 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	7	1/25/2023	NON-COMPETING CONTINUATION	$601,533
2023	2020	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	1/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $601,533

Issue Date FY: 2022 ( Subtotal = $616,561 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	6	1/27/2022	COMPETING CONTINUATION	$616,561
														Subtotal = $616,561

Issue Date FY: 2020 ( Subtotal = $494,822 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	5/8/2020	NON-COMPETING CONTINUATION	$494,822
														Subtotal = $494,822

Issue Date FY: 2019 ( Subtotal = $494,822 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	5/16/2019	NON-COMPETING CONTINUATION	$494,822
														Subtotal = $494,822

Issue Date FY: 2018 ( Subtotal = $489,059 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	5/15/2018	NON-COMPETING CONTINUATION	$489,059
														Subtotal = $489,059

Issue Date FY: 2017 ( Subtotal = $509,609 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	5/25/2017	NON-COMPETING CONTINUATION	$509,609
														Subtotal = $509,609

Issue Date FY: 2016 ( Subtotal = $517,789 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	6/1/2016	NEW	$517,789
														Subtotal = $517,789

Grand Total All Awards = $4,265,650

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Defining the role of the RNA modification N6-methyladenosine during Flaviviridae virus infection

Award Number: R01AI125416

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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