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DeADP-ribosylation of host targets mediated by a bacterial effector

Award Number: R21AI171709
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: 01/19/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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DeADP-ribosylation of host targets mediated by a bacterial effector - The pathogenic bacteria Legionella pneumophila (Lp), the causative agent of Legionnaires’ disease, injects nearly 330 effectors using its Dot/Icm protein secretion system into host cytosol to remodel cellular processes toward creating and maintaining a replicative organelle called the legionella-containing vacuole (LCV). Research in the last few years has shown some remarkable examples of ubiquitination chemistry catalyzed by some of these effectors that are unparalleled in the eukaryotic world. Two notable examples of ubiquitination of host targets have been identified where the mechanisms are independent of and radically different from the eukaryotic E1-E2-E3 system. This has added an exciting new layer of complexity to ubiquitin (Ub) manipulation by Lp, which was already known to possess several classical Ub E3 ligases and deubiquitinases among its effectors. This raises a question as to how far and deep Legionella’s manipulation of the host ubiquitin goes. Are there additional new Ub-manipulating proteins/enzymes in the large effector arsenal of the bacteria? We have performed an activity-based enrichment analysis to identify novel Ub-interacting proteins among Lp effectors to address this question. We have used Ub-derived activity-based probes (Ub-ABPs) to enrich proteins from the soluble proteome of Lp and have identified candidates using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). This has led us to the Dot/Icm substrate MavL, with unknown biochemical and biological function, as a novel Ub-interacting effector. On further analysis, we find that MavL is a deADP-ribosyl glycohydrolase capable of removing ADP-ribose (ADPR) from an arginine side chain of ADP-ribosylated Ub (ADPR-Ub). We will use a proximity labeling biotinylation strategy implemented under infection conditions to capture MavL substrates. To complement this strategy, we will engineer an inactive mutant of the enzyme into an affinity tool for proteome-wide enrichment and identification of MavL interactors from host cells. Combining information from the proteomics datasets, we aim to arrive at a list of candidates which will be validated in cell-based assays under infection conditions. Further, we will try to provide the structural basis of Ub recognition by this novel pathogenic effector. Taken together, we will be able to characterize a unique Ub-recognizing deADP-ribosylating enzyme from a pathogenic bacterium and explore its host targets, thereby expanding the scope of reversible ADP-ribosylation in host-pathogen interaction.


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: 2025 ( Subtotal = $0 )
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	11/19/2024	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	5/16/2024	NON-COMPETING CONTINUATION	$19,625
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	$176,625
														Subtotal = $196,250

Issue Date FY: 2023 ( Subtotal = $229,276 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	1/19/2023	NEW	$229,276
														Subtotal = $229,276

Grand Total All Awards = $425,526

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DeADP-ribosylation of host targets mediated by a bacterial effector

Award Number: R21AI171709

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: 01/19/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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