Orchestration of morphogenesis in filamentous fungi: conserved roles for Ras signaling networks

Fortwendel, Jarrod R.

doi:10.1016/j.fbr.2015.04.003

Cited by 21 publications

(17 citation statements)

References 52 publications

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“…In the human pathogenic fungus Aspergillus fumigatus , two Ras proteins are produced: one with high similarity to the human HRas, designated RasA, and a second homolog, designated RasB, that is produced by filamentous fungi only ( Fortwendel et al, 2004 ). Both proteins have unique and overlapping functions in mediating fungal growth, morphogenesis, and pathogenesis (reviewed in detail by Fortwendel, 2012 , 2015 ). Because of its major functions in fungal growth and pathogenesis, we have studied RasA extensively and have shown RasA to primarily localize to the plasma membrane ( Fortwendel et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA in Aspergillus fumigatus

et al. 2018

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RasA is a major regulator of fungal morphogenesis and virulence in Aspergillus fumigatus. The proper localization of RasA to the plasma membrane is essential for the formation of invasive hyphae during infection. In yeast, the localization of Ras2p to the plasma membrane is orchestrated by several post-translational modifications (PTM) at the C-terminal CAAX box that are thought to occur in sequential order. These PTMs include: (1) CAAX motif farnesylation by the farnesyltransferase complex composed of Ram1p and Ram2p; (2) proteolysis of the -AAX residues by Rce1p or Ste24p; (3) methylation of the remaining prenylated cysteine residue by Ste14p, and; (4) palmitoylation at a single conserved cysteine residue mediated by the Erf2p/Erf4p palmitoyltransferase. We previously reported that homologs of each RasA PTM enzyme are conserved in A. fumigatus. Additionally, we delineated a major role for protein farnesylation in A. fumigatus growth and virulence. In this work, we characterize the post-prenylation processing enzymes of RasA in A. fumigatus. The genes encoding the RasA post-prenylation enzymes were first deleted and examined for their roles in growth and regulation of RasA. Only when strains lacked cppB, the A. fumigatus homologue of yeast RCE1, there was a significant reduction in fungal growth and conidial germination. In addition, cppB-deletion mutants displayed hypersensitivity to the cell wall-perturbing agents Calcofluor White and Congo Red and the cell wall biosynthesis inhibitor Caspofungin. In contrast to the previously published data in yeast, the deletion of post-prenylation modifying enzymes did not alter the plasma membrane localization or activation of RasA. To delineate the molecular mechanisms underlying these differences, we investigated the interplay between dual-palmitoylation of the RasA hypervariable region and CAAX proteolysis for stabilization of RasA at the plasma membrane. Our data indicate that, in the absence of proper CAAX proteolysis, RasA accumulation at the plasma membrane is stabilized by dual palmitoyl groups on the dual cysteine residues. Therefore, we conclude CAAX proteolysis and dual-palmitoylation of the hypervariable region is important for maintaining a stable attachment association of RasA with the plasma membrane to support optimal fungal growth and development.

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Section: Introductionmentioning

confidence: 99%

C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA in Aspergillus fumigatus

et al. 2018

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“…Interestingly, GefC homologues were only identified in this study in organisms that express homologues of A . fumigatus RasB (Fortwendel, ; Fortwendel et al, ). Finally, GefD is an LTE‐class RasGEF, showing homology to Lte1p from S .…”

Section: Resultsmentioning

confidence: 99%

“…cerevisiae or C. albicans , and A . fumigatus is that filamentous organisms encode two distinct Ras subfamily members (Fortwendel, ). In A .…”

Section: Discussionmentioning

confidence: 99%

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SH3‐class Ras guanine nucleotide exchange factors are essential forAspergillus fumigatusinvasive growth

Martín‐Vicente

Souza

Abdallah

et al. 2019

Cellular Microbiology

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Proper hyphal morphogenesis is essential for the establishment and progression of invasive disease caused by filamentous fungi. In the human pathogen Aspergillus fumigatus, signalling cascades driven by Ras and Ras‐like proteins orchestrate a wide variety of cellular processes required for hyphal growth. For activation, these proteins require interactions with Ras‐subfamily‐specific guanine nucleotide exchange factors (RasGEFs). Although Ras‐protein networks are essential for virulence in all pathogenic fungi, the importance of RasGEF proteins is largely unexplored. A. fumigatus encodes four putative RasGEFs that represent three separate classes of RasGEF proteins (SH3‐, Ras guanyl nucleotide‐releasing protein [RasGRP]–, and LTE‐class), each with fungus‐specific attributes. Here, we show that the SH3‐class and RasGRP‐class RasGEFs are required for properly timed polarity establishment during early growth and branch emergence as well as for cell wall stability. Further, we show that SH3‐class RasGEF activity is essential for polarity establishment and maintenance, a phenotype that is, at least, partially independent of the major A. fumigatus Ras proteins, RasA and RasB. Finally, loss of both SH3‐class RasGEFs resulted in avirulence in multiple models of invasive aspergillosis. Together, our findings suggest that RasGEF activity is essential for the integration of multiple signalling networks to drive invasive growth in A. fumigatus.

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“…Similarly, the present analysis showed Apophysomyces genomes had multiple paralog gene clusters of protein kinase. The Ras protein regulates eukaryotic growth and differentiation, and orchestrates virulence in pathogenic fungi [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Apophysomyces variabilis: draft genome sequence and comparison of predictive virulence determinants with other medically important Mucorales

et al. 2017

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Background Apophysomyces species are prevalent in tropical countries and A. variabilis is the second most frequent agent causing mucormycosis in India. Among Apophysomyces species, A. elegans, A. trapeziformis and A. variabilis are commonly incriminated in human infections. The genome sequences of A. elegans and A. trapeziformis are available in public database, but not A. variabilis. We, therefore, performed the whole genome sequence of A. variabilis to explore its genomic structure and possible genes determining the virulence of the organism.ResultsThe whole genome of A. variabilis NCCPF 102052 was sequenced and the genomic structure of A. variabilis was compared with already available genome structures of A. elegans, A. trapeziformis and other medically important Mucorales. The total size of genome assembly of A. variabilis was 39.38 Mb with 12,764 protein-coding genes. The transposable elements (TEs) were low in Apophysomyces genome and the retrotransposon Ty3-gypsy was the common TE. Phylogenetically, Apophysomyces species were grouped closely with Phycomyces blakesleeanus. OrthoMCL analysis revealed 3025 orthologues proteins, which were common in those three pathogenic Apophysomyces species. Expansion of multiple gene families/duplication was observed in Apophysomyces genomes. Approximately 6% of Apophysomyces genes were predicted to be associated with virulence on PHIbase analysis. The virulence determinants included the protein families of CotH proteins (invasins), proteases, iron utilisation pathways, siderophores and signal transduction pathways. Serine proteases were the major group of proteases found in all Apophysomyces genomes. The carbohydrate active enzymes (CAZymes) constitute the majority of the secretory proteins.ConclusionThe present study is the maiden attempt to sequence and analyze the genomic structure of A. variabilis. Together with available genome sequence of A. elegans and A. trapeziformis, the study helped to indicate the possible virulence determinants of pathogenic Apophysomyces species. The presence of unique CAZymes in cell wall might be exploited in future for antifungal drug development.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4136-1) contains supplementary material, which is available to authorized users.

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Orchestration of morphogenesis in filamentous fungi: conserved roles for Ras signaling networks

Cited by 21 publications

References 52 publications

C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA in Aspergillus fumigatus

C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA in Aspergillus fumigatus

SH3‐class Ras guanine nucleotide exchange factors are essential forAspergillus fumigatusinvasive growth

Apophysomyces variabilis: draft genome sequence and comparison of predictive virulence determinants with other medically important Mucorales

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