Abstract
The regulator of G protein signaling (RGS) domain proteins generally attenuate heterotrimeric G protein signaling, thereby fine-tune the duration and strength of signal transduction. In this study, we characterize the functions of RgsD, one of the six RGS domain proteins present in the human pathogenic fungus Aspergillus fumigatus. The deletion (Δ) of rgsD results in enhanced asexual sporulation coupled with increased mRNA levels of key developmental activators. Moreover, ΔrgsD leads to increased spore tolerance to UV and oxidative stress, which might be associated with the enhanced expression of melanin biosynthetic genes and increased amount of melanin. Yeast two-hybrid assays reveal that RgsD can interact with the three Gα proteins GpaB, GanA, and GpaA, showing the highest interaction potential with GpaB. Importantly, the ΔrgsD mutant shows elevated expression of genes in the cAMP-dependent protein kinase A (PKA) pathway and PKA catalytic activity. The ΔrgsD mutant also display increased gliotoxin production and elevated virulence toward Galleria mellonella wax moth larvae. Transcriptomic analyses using RNA-seq reveal the expression changes associated with the diverse phenotypic outcomes caused by ΔrgsD. Collectively, we conclude that RgsD attenuates cAMP-PKA signaling pathway and negatively regulates asexual development, toxigenesis, melanin production, and virulence in A. fumigatus.
Highlights
All living cells must adapt or respond to external and internal cues
Revealed that RgsC is necessary for proper growth, sporulation, stress response, gliotoxin (GT) production, and external nutrients sensing in A. fumigatus[12]
Regulator of G protein signaling (RGS) proteins are GTPase accelerating proteins (GAPs) that act as negative regulators of multifunctional signaling in many fungi[10,11,12,14,26,27]
Summary
All living cells must adapt or respond to external and internal cues. In cells, environmental cues trigger intrinsic signaling cascades involving a variety of surface receptors and signal transduction elements. The second RGS of S. cerevisiae Rgs[2] attenuates the Gpa2-mediated signaling for glucose sensing through controlling the cAMP-dependent protein kinase (PKA) pathway[7]. RGSs of filamentous fungi regulate diverse signals that control vegetative growth, sporulation, stress responses, secondary metabolism, and virulence[9]. There are six RGS proteins (FlbA, GprK, RgsA, Rax[1], RgsC, and RgsD) in the opportunistic human pathogen Aspergillus fumigatus. We have revealed that FlbA, GprK, and Rax[1] play important roles in upstream regulation of G-protein and contribute to proper asexual development, secondary metabolites production, and stress responses[10,11] our recent study has www.nature.com/scientificreports/. Revealed that RgsC is necessary for proper growth, sporulation, stress response, gliotoxin (GT) production, and external nutrients sensing in A. fumigatus[12]. Understanding the target(s) of RgsD and downstream signaling cascades would provide a development of novel anti-fungal therapeutics against A. fumigatus
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