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Role of DDX5 in Hepatitis B virus transcription and hepatocarcinogenesis

Award Number: R21AI170712
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/16/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Role of DDX5 in Hepatitis B virus transcription and hepatocarcinogenesis - Abstract This proposal investigates the role of the RNA helicase DDX5/p68 in regulating immune signaling pathways and gene expression, as it relates to hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma (HCC). Our earlier studies demonstrated that DDX5 is a host restriction factor in HBV biosynthesis by a mechanism not yet understood, that DDX5 is downregulated in HBV-related HCC with poor prognosis and in response to multi-kinase inhibitors (mTKIs) used for the treatment of advanced HCC, and that DDX5 controls STAT1 translation. Our RNAseq analyses of human liver cancer cell lines exhibiting DDX5 knockdown, identified activation of Wnt and non-canonical NF-κB signaling, as downstream targets of DDX5. To gain further insight into the mechanism of DDX5 action in terms of virus biosynthesis and liver cancer pathogenesis, we performed a proteomics (LC-MS/MS) study to identify cellular interacting partners of DDX5. Surprisingly, our studies identified the Interferon gamma induced protein 16 (IFI16), a nuclear DNA sensor and restriction factor for viruses that replicate in the nucleus, as the most prominent cellular factor interacting with DDX5. A recent study has demonstrated that IFI16 binds the HBV minichromosome leading to inhibition of HBV replication. However, HBV downregulates IFI16 expression as a strategy to escape innate immune surveillance in chronically HBV infected patients. Significantly, the role of DDX5 in this interaction is currently unknown. Our results based on chromatography of native nuclear extracts followed by label-free quantitative MS profiling show that DDX5 and IFI16 co-eluted with auxiliary and core PRC2 subunits, HDAC1, 2 and DNMT1. This is consistent with the prediction using the CORUM database, that DDX5/IFI16 interact with the MeCP1 complex, comprised of histone deacetylases (HDACs) & DNA methyl transferases (DNMTs), and the chromatin silencing Polycomb Repressive Complex 2 (PRC2). Importantly, treatment of nuclear lysates with recombinant nuclease benzonase reduced association of DDX5 with IFI16, suggesting involvement of an RNA in the formation of this complex. However, the RNA substrate involved in formation of the DDX5/IFI16 complex is currently unknown. Based on these preliminary observations, we hypothesize that the DDX5/IFI16 complex represses viral transcription, as well as cellular transcription of genes important for HCC progression. To address this hypothesis we propose two independent specific aims focusing on key aspects of this mechanism: Aim1: To determine the antiviral effect of the epigenetic DDX5/IFI16 silencing complex. Aim2: To determine the role of the DDX5/IFI16 complex in the expression of liver cancer genes. Impact: Successful completion of this project will identify an essential mechanism as a therapeutic target for silencing transcription from the HBV minichromosome, and reversing cellular gene expression changes associated with poor prognosis HBV-related liver cancer.


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: 2026 ( Subtotal = $0 )
2026	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	2/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	12/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $196,250 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	001	2	5/22/2024	NON-COMPETING CONTINUATION	$19,625
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$176,625
														Subtotal = $196,250

Issue Date FY: 2023 ( Subtotal = $227,309 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	2/16/2023	NEW	$227,309
														Subtotal = $227,309

Grand Total All Awards = $423,559

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Role of DDX5 in Hepatitis B virus transcription and hepatocarcinogenesis

Award Number: R21AI170712

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/16/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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