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Arrestin proteins mediate microbial cellular adaptation and fungal virulence

Award Number: R21AI153799
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: 04/21/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Arrestin proteins mediate microbial cellular adaptation and fungal virulence - Abstract In order to effectively cause disease, microorganisms must continuously sense and respond to rapidly changing environments. For microbial pathogens, these adaptive cellular processes include the ability to respond to host-derived stresses. The robustness with which microorganisms regulate these adaptive responses largely determines their ability to survive within the infected host. In the experiments outlined in this proposal, we build upon recent and converging data from our laboratory supporting the importance of protein ubiquitination in microbial host responses. Originally defined for directing proteins for degradation, ubiquitination is increasingly recognized as a means of precise regulation of the localization and function of many target proteins. In the human fungal pathogen Cryptococcus neoformans, we have identified the Rsp5 ubiquitin ligase as a key mediator of stress response and virulence. Our preliminary experiments have begun to define the specific aspects of the pathogenic process that require Rsp5 activity, including cell wall homeostasis and cell cycle progression. Consistent with emerging models of ubiquitination in diverse species, our experimental results suggest that Rsp5 is directed to its protein targets by adaptor proteins, including the arrestin protein family. Our initial in vitro and in vivo experiments indicate that the virulence- associated phenotypes of the C. neoformans rsp5 mutant are likely a composite of individual contribution of altered target protein function. By further defining the microbial ubiquitin ligase / adaptor / target protein axis, we will more deeply explore the mechanisms by which stress-induced cellular responses influence fungal infections.


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 = -$8,575 )
2025	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	6/3/2025	NON-COMPETING CONTINUATION	-$8,575
														Subtotal = -$8,575

Issue Date FY: 2023 ( Subtotal = $201,250 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	4/10/2023	NON-COMPETING CONTINUATION	$201,250
														Subtotal = $201,250

Issue Date FY: 2022 ( Subtotal = $241,500 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	4/21/2022	NEW	$241,500
														Subtotal = $241,500

Grand Total All Awards = $434,175

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Arrestin proteins mediate microbial cellular adaptation and fungal virulence

Award Number: R21AI153799

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: 04/21/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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