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Exploiting bacterial effector proteins to study human ubiquitin signaling

Award Number: R35GM142486
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Exploiting bacterial effector proteins to study human ubiquitin signaling - Project Summary Post-translational signaling through ubiquitination is essential to all eukaryotic life, and dysregulation of this process can lead to severe forms of disease. The far-reaching importance of ubiquitin signaling across many cellular processes stems from its ability to form a diverse set of polymeric chains that signal for distinct outcomes. The complexity of ubiquitin signaling vastly outweighs our understanding of its regulation and cellular outcomes. While the signaling roles for some ubiquitin chain types are known (e.g., protein degradation or cell cycle regulation), the functions of many so-called `atypical' chains have remained a mystery despite decades of research, and emerging roles for `noncanonical' and Ub-like modifications have added further complexity. As an alternative approach to studying fundamental human biology, we study the interactions between invading pathogenic bacteria and the host ubiquitin signaling network. To support infection, bacteria have evolved secreted effector proteins to assemble and remove host ubiquitin signals, in some cases with exquisite specificity. We have demonstrated that ubiquitin-targeted bacterial effectors represent a rich opportunity to study human ubiquitin signaling from an `outside-in' perspective. To explore this opportunity, we have developed a multipronged approach that has identified novel ubiquitin-targeted activities among important bacterial pathogens. Using structural and biochemical approaches we will explain the mechanisms and specificities of these bacterial enzymes, at which point they will be used as case studies and tools to extend our work toward deciphering the regulatory and signaling complexities of the human ubiquitin system. Our innovative approach to studying ubiquitin biology plays to our strengths in the biochemical mechanisms of its regulation, and leverages the strong evolutionary pressure placed on bacteria to usurp specific aspects of host ubiquitin signaling. Over the next five years we will expand upon the breadth of bacterial ubiquitin-targeted activities and their utility for dissecting the intricacies of ubiquitin signaling, which feeds into our larger vision of understanding the motivations and ramifications of bacterial interference in host signaling processes.


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 = $429,000 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	6	5/18/2026	COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2025 ( Subtotal = $385,000 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	5	5/20/2025	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $434,811 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	4	5/9/2024	NON-COMPETING CONTINUATION	$385,000
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	4	5/10/2024	SUPPLEMENT FOR EXPANSION	$49,811
														Subtotal = $434,811

Issue Date FY: 2023 ( Subtotal = $385,000 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	3	5/26/2023	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2022 ( Subtotal = $549,542 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	2	5/20/2022	NON-COMPETING CONTINUATION	$385,000
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	2	5/24/2022	SUPPLEMENT FOR EXPANSION	$164,542
														Subtotal = $549,542

Issue Date FY: 2021 ( Subtotal = $385,000 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	1	6/22/2021	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $2,568,353

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Exploiting bacterial effector proteins to study human ubiquitin signaling

Award Number: R35GM142486

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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