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Manipulation of host immunity by a bacterial E3 ubiquitin ligase

Award Number: R01GM078021
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: 05/01/2006
PERIOD OF PERFORMANCE END DATE: 12/31/2014

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Manipulation of host immunity by a bacterial E3 ubiquitin ligase - DESCRIPTION (provided by applicant): Bacterial pathogens of both plants and humans use a type III secretion system to inject effector proteins into the cells of their hosts. As many as 30 or more different 'type III effectors' can be delivered by an individual pathogen and once inside the host cell they manipulate various processes to promote bacterial virulence. The great diversity of type III effectors, and the fact that their amino acid sequences offer few clues to their function, has been an impediment to understanding how they manipulate the host. One host process, the attachment of ubiquitin to a protein in order to regulate its function or to cause its degradation, plays an important role in host immunity and offers a vulnerable target for type III effectors. This application concerns the characterization of a type III effector, AvrPtoB, from the plant pathogen Pseudomonas syringae. The crystal structure of a C-terminal domain of AvrPtoB revealed that it is a structural mimic of the U-box class of E3 ubiquitin ligases - a type of host protein that facilitates the attachment of ubiquitin to other proteins. The AvrPtoB E3 ligase is able to use host E2 conjugating enzymes to cause ubiquitination and degradation of a host protein kinase required for immunity. Despite these advances, much remains to be learned about how this bacterial E3 ligase binds and ubiquitinates its host substrates in order to subvert their normal functions. Recently virulence proteins from human pathogens such as Legionella pneumophila and Escherichia coli have also been found to express proteins of the U-box class of E3 ligases. Structural mimicry of this type of host protein therefore appears to be a common strategy for undermining host immunity. The long term objective of this project is to increase our understanding of the underlying mechanisms that bacterial E3 ligases use to manipulate host ubiquitination. This knowledge will be useful for the development of novel strategies for interfering with these virulence proteins in order to lessen the impact of pathogen infection in both plants and humans. The goals of this application are to: 1) Identify the host E2 conjugating enzyme used by AvrPtoB and characterize the role of a ubiquitin-interaction motif that lies close to the U-box; 2) Exploit the recently solved crystal structure of AvrPtoB in complex with one of its host targets to understand how AvrPtoB recognizes and binds its substrates; 3) Perform a screen to identify additional host proteins that AvrPtoB ubiquitinates and which are candidates for playing a role in host immunity; 4) Investigate the way in which certain host-mediated modifications of AvrPtoB (e.g. phosphorylation) influence its E3 ligase activity; and 5) Develop a method to visually monitor the delivery of AvrPtoB into the host cell. The method will be used to test the hypothesis that type III effectors that act early in the infection process are delivered before later-acting effectors.


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: 2014 ( Subtotal = $230,475 )
2014	2014	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	001	8	3/24/2014	NON-COMPETING CONTINUATION	$23,047
2014	2014	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	8	1/13/2014	NON-COMPETING CONTINUATION	$207,428
														Subtotal = $230,475

Issue Date FY: 2013 ( Subtotal = $222,408 )
2013	2013	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	001	7	6/27/2013	NON-COMPETING CONTINUATION	$14,980
2013	2013	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	7	12/20/2012	NON-COMPETING CONTINUATION	$207,428
														Subtotal = $222,408

Issue Date FY: 2012 ( Subtotal = $230,475 )
2012	2012	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	001	6	3/1/2012	NON-COMPETING CONTINUATION	$23,047
2012	2012	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	6	12/27/2011	NON-COMPETING CONTINUATION	$207,428
														Subtotal = $230,475

Issue Date FY: 2011 ( Subtotal = $230,475 )
2011	2011	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	001	5	1/24/2011	COMPETING CONTINUATION	$230,475
2011	2009	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	4	1/24/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $230,475

Issue Date FY: 2009 ( Subtotal = $211,797 )
2009	2009	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	4	4/27/2009	NON-COMPETING CONTINUATION	$211,797
														Subtotal = $211,797

Issue Date FY: 2008 ( Subtotal = $211,797 )
2008	2008	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	3	4/14/2008	NON-COMPETING CONTINUATION	$211,797
														Subtotal = $211,797

Issue Date FY: 2007 ( Subtotal = $211,797 )
2007	2007	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	2	5/9/2007	NON-COMPETING CONTINUATION	$211,797
														Subtotal = $211,797

Issue Date FY: 2006 ( Subtotal = $218,122 )
2006	2006	BOYCE THOMPSON INSTITUTE FOR PLANT RESEARCH	TOWER ROAD	ITHACA	NY	14853	TOMPKINS	USA	Biomedical Research and Research Training	000	1	4/17/2006	NEW	$218,122
														Subtotal = $218,122

Grand Total All Awards = $1,767,346

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Manipulation of host immunity by a bacterial E3 ubiquitin ligase

Award Number: R01GM078021

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: 05/01/2006

PERIOD OF PERFORMANCE END DATE: 12/31/2014

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