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Suppression mechanism of Geminivirus-encoded TrAP protein

Award Number: R01GM127742
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/21/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Suppression mechanism of Geminivirus-encoded TrAP protein - The primary goal of the proposed research is to elucidate the mechanism of host innate immune responses and viral counter-defense responses at an epigenetic level. Eukaryotes have evolved sophisticated mechanisms of RNA silencing to defense invasive viruses. On the other hand, viruses including those infecting humans encode proteins, referred to as viral suppressors, to block silencing pathways to evade host surveillance. The prevailing worldwide study on host-virus interaction focuses on the antivirus role of posttranscriptional gene silencing (PTGS) and viral suppression of PTGS. While our knowledge of viral suppression at the PTGS level has been drastically expanded, our understanding of viral suppression at the level of transcriptional gene silencing (TGS) is very poor. In eukaryotes, the nuclear DNA is wrapped onto histone octamers to form a chromatin. Chromatin methylation not only regulates gene replication and transcription, but also controls the latency of viruses in human and plants, functioning as an innate immune system to restrict invasive pathogens. Recent research from the PI's group and other laboratories has illuminated that TrAP suppressor encoded by Geminivirus, a family of single-stranded DNA viruses in the model organism Arabidopsis, genetically interferes with the TGS pathway. By proteomic screening of cellular factors, the PI's group has identified that a histone methyltransferase (SUVH4) and a histone demethylase (REF6), two key effectors in the TGS pathway, are new bona fide targets by TrAP. These results and work from several other groups led to conceptualization of a model that TGS serves as a defense mechanism to defend invasive DNA pathogens, whereas viral suppressors can break this restriction by directly inhibiting the TGS integrators. To address this model, the PI proposes: 1) to determine the biochemical basis for specific inhibitory effect of TrAP on SUVH. The PI wishes to pinpoint the critical residues of TrAP that participate in the interaction with SUVH4 and investigate how the residues affect SUVH4 function and alter the viral pathogenicity; The PI will also study whether TrAP targets the genetic paralogs of SUVH4 such as SUVH5 and SUVH6 to regulate Geminivirus infection; and 2) to investigate function and mechanism of TrAP-REF6 interaction in viral infection. The PI laboratory has observed that REF6 binds to Geminivirus chromatin and loss-of-function mutants of ref6 exhibit reduced susceptibility to Geminivirus infection. The PI plans to systemically study the biochemical features of REF6 and its functional interaction of TrAP in viral transcription and multiplication. The proposed study will address the fundamental but poorly understood mechanism how histone methyltransferases and demethylases coordinately confer viral latency and how DNA virus co-opts to hijack the critical TGS components as counter-defense responses. The suppression mechanism of TrAP may be exploited for directed therapies or preventative measures to address physiological disorders that arise from epigenetic dysfunction in eukaryotes including human.


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 = -$40,758 )
2024	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	4	5/30/2024	NON-COMPETING CONTINUATION	-$40,758
														Subtotal = -$40,758

Issue Date FY: 2022 ( Subtotal = $293,288 )
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	4	11/10/2021	NON-COMPETING CONTINUATION	$263,959
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	4	6/27/2022	NON-COMPETING CONTINUATION	$29,329
														Subtotal = $293,288

Issue Date FY: 2021 ( Subtotal = $336,433 )
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	3	2/26/2021	NON-COMPETING CONTINUATION	$29,329
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	10/30/2020	NON-COMPETING CONTINUATION	$263,959
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	002	3	8/24/2021	SUPPLEMENT FOR EXPANSION	$43,145
														Subtotal = $336,433

Issue Date FY: 2020 ( Subtotal = $293,288 )
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	2	11/21/2019	NON-COMPETING CONTINUATION	$263,959
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	2	3/10/2020	NON-COMPETING CONTINUATION	$29,329
														Subtotal = $293,288

Issue Date FY: 2019 ( Subtotal = $293,288 )
2019	2019	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	1	12/21/2018	NEW	$293,288
														Subtotal = $293,288

Grand Total All Awards = $1,175,539

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Suppression mechanism of Geminivirus-encoded TrAP protein

Award Number: R01GM127742

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/21/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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