Friday, April 19, 2024
4/19/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
