A non-canonical RNAi pathway controls virulence and genome stability in Mucorales

Pérez-Arques, Carlos; Navarro-Mendoza, María Isabel; Murcia, Laura; Navarro, Eusebio; Garre, Victoriano

doi:10.1371/journal.pgen.1008611

Cited by 25 publications

(62 citation statements)

References 40 publications

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“…Transcriptomics on rdrp1 and r3b2 mutants demonstrated that these genes play important roles in regulating the fungal response to stressful environments, such as macrophage phagocytosis, as well as movement of TEs. These results that NCRIP play a role in controlling virulence in M. circinelloides ( Pérez-Arques et al, 2020 ).…”

Section: Insights Into Mucorales Biology and Virulmentioning

confidence: 81%

Understanding Mucormycoses in the Age of “omics”

2020

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Mucormycoses are deadly invasive infections caused by several fungal species belonging to the subphylum Mucoromycotina, order Mucorales. Hallmarks of disease progression include angioinvasion and tissue necrosis that aid in fungal dissemination through the blood stream, causing deeper infections and resulting in poor penetration of antifungal agents to the site of infection. In the absence of surgical removal of the infected focus, antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose antifungal therapy, the mortality associated with mucormycoses is >50%. The unacceptably high mortality rate, limited options for therapy and the extreme morbidity of highly disfiguring surgical therapy provide a clear mandate to understand the molecular mechanisms that govern pathogenesis with the hopes of developing alternative strategies to treat and prevent mucormycoses. In the absence of robust forward and reverse genetic systems available for this taxonomic group of fungi, unbiased next generation sequence (NGS)-based approaches have provided much needed insights into our understanding of many aspects of Mucormycoses, including genome structure, drug resistance, diagnostic development, and fungus-host interactions. Here, we will discuss the specific contributions that NGSbased approaches have made to the field and discuss open questions that can be addressed using similar approaches.

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Section: Insights Into Mucorales Biology and Virulmentioning

confidence: 81%

Understanding Mucormycoses in the Age of “omics”

2020

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“…The canonical RNAi pathway negatively regulates theses sequences, as mutant strains lacking RNAi typical components (Ago1, Dcl1, and Dcl2) show a decrease in sRNA levels targeting Grem-LINE and, consequently, increased Grem-LINE mRNA expression. Surprisingly, mutant strains lacking proteins (RdRP1 and R3B2) of a different pathway known as noncanonical RNAi pathway (NCRIP) show enhanced levels of Grem-LINE1 sRNAs compared to the wild-type strain [ 64 ]. Therefore, the NCRIP regulates the silencing of these Grem-LINE1 through the modulation of the canonical mechanism [ 64 ].…”

Section: Control Of Transposable Elementsmentioning

confidence: 99%

“…Surprisingly, mutant strains lacking proteins (RdRP1 and R3B2) of a different pathway known as noncanonical RNAi pathway (NCRIP) show enhanced levels of Grem-LINE1 sRNAs compared to the wild-type strain [ 64 ]. Therefore, the NCRIP regulates the silencing of these Grem-LINE1 through the modulation of the canonical mechanism [ 64 ].…”

Section: Control Of Transposable Elementsmentioning

confidence: 99%

“…This mechanism was initially described as a gene regulation pathway implicated in oxidative stress and sexual interaction [ 23 , 43 ]. Additionally, the latest studies established that NCRIP regulates more than 25% of the genome, 3187 genes mostly linked to cellular metabolism, germination, and development, indicating a relevant role in saprophytic growth conditions [ 64 ]. Furthermore, the transcriptomic profile of M. lusitanicus during phagocytosis is similar to that of mutant strains lacking NCRIP [ 64 , 101 ], suggesting that this mechanism is repressing the genetic program of defense against phagocytosis.…”

Section: Regulation Of Endogenous Genesmentioning

confidence: 99%

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The Evolutionary Significance of RNAi in the Fungal Kingdom

Lax

Tahiri

Patiño-Medina

et al. 2020

IJMS

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RNA interference (RNAi) was discovered at the end of last millennium, changing the way scientists understood regulation of gene expression. Within the following two decades, a variety of different RNAi mechanisms were found in eukaryotes, reflecting the evolutive diversity that RNAi entails. The essential silencing mechanism consists of an RNase III enzyme called Dicer that cleaves double-stranded RNA (dsRNA) generating small interfering RNAs (siRNAs), a hallmark of RNAi. These siRNAs are loaded into the RNA-induced silencing complex (RISC) triggering the cleavage of complementary messenger RNAs by the Argonaute protein, the main component of the complex. Consequently, the expression of target genes is silenced. This mechanism has been thoroughly studied in fungi due to their proximity to the animal phylum and the conservation of the RNAi mechanism from lower to higher eukaryotes. However, the role and even the presence of RNAi differ across the fungal kingdom, as it has evolved adapting to the particularities and needs of each species. Fungi have exploited RNAi to regulate a variety of cell activities as different as defense against exogenous and potentially harmful DNA, genome integrity, development, drug tolerance, or virulence. This pathway has offered versatility to fungi through evolution, favoring the enormous diversity this kingdom comprises.

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“…Different research lines study the role of virulence factors described in Mucorales pathogenesis, such as the CotH proteins, the three components of the high-affinity iron uptake system, and the regulatory proteins involved in dimorphism [13][14][15][16][17]. In addition, several genomewide strategies have been designed to find new and specific targets in Mucorales, based on the RNAi mechanism of the fungus [18] and in the host-pathogen transcriptome [19,20]. This work aims to study the role of the white-collar-1 (wc-1) genes in the virulence of Mucorales as master regulators controlling many pathways that could represent new promising targets.…”

Section: Introductionmentioning

confidence: 99%

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene-Network during Host Interactions.

Arques¹,

Mendoza²,

Murcia³

et al. 2020

Preprint

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Mucolares are an ancient group of fungi encompassing the causal agents for the lethal infection mucormycosis. The high lethality rates, the emerging character of this disease, and the broad antifungal resistance of its causal agents are mucormycosis features alarming clinicians and researchers. Thus, the research field around mucormycosis is currently focused on finding specific weaknesses and targets in Mucorales for developing new treatments against mucormycosis. In this work, we tested the role of the white-collar genes family in the virulence potential of Mucor lusitanicus. In this regard, the study of the role in virulence of the three genes of this family, mcwc-1a, mcwc-1b, and mcwc-1c, resulted in a marked functional specialization, as only mcwc-1a was essential to maintain the virulence potential of M. lusitanicus. The traditional role of wc-1 genes regulating light-dependent responses is a thoroughly studied field, whereas their role in virulence remains uncharacterized. In this work, we investigated the mechanism involving mcwc-1a in virulence from an integrated transcriptomic and functional approach during the host-pathogen interaction. Our results revealed mcwc-1a as a master regulator controlling an extensive gene-network. Further dissection of this gene-network clustering its components by type of regulation and functional criteria disclosed a multifunctional mechanism depending on diverse pathways. In the absence of phagocytic cells, mcwc-1a controlled pathways related to cell motility and cytoskeleton that could be associated with the essential tropism during tissue invasion. After phagocytosis, several oxidative responding pathways dependent on mcwc-1a were activated during the germination of M. lusitanicus spore inside of phagocytic cells, which is the first stage of the infection. The third relevant group of genes involved in virulence and regulated by mcwc-1a belonged to the “unknown function,” indicating that new and hidden pathways are involved in virulence. The unknown function category is especially pertinent in the study of mucormycosis, as it is highly enriched in specific fungal genes that represent the most promising targets for developing new antifungal compounds. These results essentially unveil a complex multifunctional mechanism used by wc-1 genes to regulate the pathogenic potential in Mucorales that could also apply to other fungal pathogens.

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A non-canonical RNAi pathway controls virulence and genome stability in Mucorales

Cited by 25 publications

References 40 publications

Understanding Mucormycoses in the Age of “omics”

Understanding Mucormycoses in the Age of “omics”

The Evolutionary Significance of RNAi in the Fungal Kingdom

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene-Network during Host Interactions.

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