Phylogenetic analysis of fungal heterotrimeric G protein-encoding genes and their expression during dimorphism in Mucor circinelloides

Valle-Maldonado, Marco I.; Jácome-Galarza, Irvin E.; Díaz-Pérez, Alma Laura; Martı́nez-Cadena, Guadalupe; Campos-Garcı́a, Jesús; Ramírez-Díaz, Martha I.; Cruz, Homero Reyes de la; Riveros‐Rosas, Héctor; Díaz-Pérez, César; Meza-Carmen, Víctor

doi:10.1016/j.funbio.2015.08.009

Cited by 13 publications

(29 citation statements)

References 65 publications

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“…Nevertheless, in vitro and in vivo susceptibility tests have been performed for some of the most commonly used triazole drugs in a representative group of pathogenic Mucorales such as Lichtheimia spp., Rhizopus spp., and Mucor spp. The results show an intrinsic resistance to fluconazole and voriconazole, both lacking significant in vitro activity against Mucorales [1,40,53]. However, posaconazole shows in vitro activity with MIC 50 ranging between 0.125 and 1 µg in Lichtheimia spp., 0.25 and 2 µg/mL in Rhizopus spp., and 0.5 and 2 µg/mL in Mucor spp.…”

Section: Azole Resistance In Mucoralesmentioning

confidence: 91%

“…Interestingly, calcineurin negatively regulates PKA, suggesting a relationship between these two regulatory pathways [29]. Other proteins might also be involved in the regulation of M. circinelloides dimorphism, such as heterotrimeric G proteins and the ADP-ribosylation factors (Arfs), which are differentially expressed during the dimorphism process of this fungus [39,40].…”

Section: Dimorphism Controls the Pathogenic Potential Of Mucor Circinmentioning

confidence: 99%

“…However, posaconazole shows in vitro activity with MIC 50 ranging between 0.125 and 1 µg in Lichtheimia spp., 0.25 and 2 µg/mL in Rhizopus spp., and 0.5 and 2 µg/mL in Mucor spp. [1,40,[53][54][55][56]. Also, in vivo activity for posaconazole have been reported with different efficacy among species [57].…”

Section: Azole Resistance In Mucoralesmentioning

confidence: 99%

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Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales

Lax

Pérez-Arques

Navarro-Mendoza

et al. 2020

Genes

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The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis.Genes 2020, 11, 317 2 of 17 Mucorales are a neglected phylogenetic group compared to others such as Ascomycetes and Basidiomycetes. The limited knowledge about the genetics of Mucorales is a consequence of the restricted tools for gene manipulation, as most of them cannot be transformed. However, DNA can be introduced in Mucor circinelloides, Rhizopus delemar, and Rhizopus oryzae [6,7]. These genetic models and the alarm raised for the emerging cases of mucormycosis are attracting the interest of the scientific community. Thus, the last decade has produced several studies related to genes, pathways, and mechanisms showing a direct connection with virulence in Mucorales [8,9]. One of the most studied mechanisms has been the process of gene silencing or RNA interfering (RNAi) in M. circinelloides [10]. After the dissection of the gene silencing machinery, the knowledge of this mechanism allowed the unveiling of a new and particular type of antifungal resistance mediated by temporal epigenetic changes [11]. In addition, the applied use of gene silencing enabled the development of functional genomics techniques, which have been used for the identification of several new virulence factors [12]. Along with silencing, gene disruption driven by homologous recombination has also allowed the study of the particular role in M. circinelloides of virulence factors identified in other fungi, such as the role of a high-affinity iron uptake mechanism, the protein family of CotH, and the calcineurin pathway. Moreover, the implementation of the new omics technologies has produced a long list of candidate genes not previously related to virulence, becoming promising targets for the development of new treatments against mucormycosis. Finally, the diversity of molecular and cell methodolo...

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Section: Azole Resistance In Mucoralesmentioning

confidence: 91%

Section: Dimorphism Controls the Pathogenic Potential Of Mucor Circinmentioning

confidence: 99%

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Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales

Lax

Pérez-Arques

Navarro-Mendoza

et al. 2020

Genes

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“…We previously described in M. circinelloides the most extensive repertoire of heterotrimeric G proteins in the fungal kingdom: 12 Gα, three Gβ, and three Gγ subunits (Valle-Maldonado, Jácome-Galarza, Díaz-Pérez, et al, 2015). Accordingly, it has been proposed a wholegenome duplication in Mucoromycotina fungi that could explain the increased number of genes that encode signal transduction proteins (Corrochano et al, 2016).…”

Section: The Addition Of Camp To Cultures Of Diverse Dimorphic Speciementioning

confidence: 99%

“…Phylogenetic analysis revealed the existence of four phylogenetic groups (I-IV) for fungal Gβ subunits. The three Gβ subunits (Gpb1, Gpb2 and Gpb3) encoded in the genome of M. circinelloides belong to group III, which is composed of subunits from Mucorales exclusively (Valle-Maldonado, Jácome-Galarza, Díaz-Pérez, et al, 2015). It is noteworthy that group III is the only fungal Gβ group with no members that have been functionally characterised to date.…”

Section: The Addition Of Camp To Cultures Of Diverse Dimorphic Speciementioning

confidence: 99%

The heterotrimeric G‐protein beta subunit Gpb1 controls hyphal growth under low oxygen conditions through the protein kinase A pathway and is essential for virulence in the fungusMucor circinelloides

Valle-Maldonado

Patiño-Medina

Pérez-Arques

et al. 2020

Cellular Microbiology

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Mucor circinelloides, a dimorphic opportunistic pathogen, expresses three heterotrimeric G‐protein beta subunits (Gpb1, Gpb2 and Gpb3). The Gpb1‐encoding gene is up‐regulated during mycelial growth compared with that in the spore or yeast stage. gpb1 deletion mutation analysis revealed its relevance for an adequate development during the dimorphic transition and for hyphal growth under low oxygen concentrations. Infection assays in mice indicated a phenotype with considerably reduced virulence and tissue invasiveness in the deletion mutants (Δgpb1) and decreased host inflammatory response. This finding could be attributed to the reduced filamentous growth in animal tissues compared with that of the wild‐type strain. Mutation in a regulatory subunit of cAMP‐dependent protein kinase A (PKA) subunit (PkaR1) resulted in similar phenotypes to Δgpb1. The defects exhibited by the Δgpb1 strain were genetically suppressed by pkaR1 overexpression, indicating that the PKA pathway is controlled by Gpb1 in M. circinelloides. Moreover, during growth under low oxygen levels, cAMP levels were much higher in the Δgpb1 than in the wild‐type strain, but similar to those in the ΔpkaR1 strain. These findings reveal that M. circinelloides possesses a signal transduction pathway through which the Gpb1 heterotrimeric G subunit and PkaR1 control mycelial growth in response to low oxygen levels.

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