期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2110298118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Aspergillus fumigatus gives rise to invasive aspergillosis in immunocompromised individuals. The rise of
A. fumigatus antifungal resistance threatens a limited arsenal of treatment options. Here, we use genetic and molecular approaches to dissect the contribution of the citron homology (CNH) domain of the guanine nucleotide exchange factor Rom2 in regulating the biosynthesis of the essential and unique fungal cell wall, an important target of antifungal compounds. The CNH domain plays an essential role as a stabilizer for the small GTPase Rho1, a key regulator of glucan biosynthesis. This work provides a model for their interaction, revealing a promising molecular mechanism to explore in the quest for novel antifungal compounds.
Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1–Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.
