The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals

Tucey, Timothy M.; Verma-Gaur, Jiyoti; Nguyen, Julie; Hewitt, Victoria L.; Lo, Tricia L.; Shingú-Vázquez, Miguel; Robertson, Avril A. B.; Hill, J. R.; Pettolino, Filomena; Beddoe, Travis; Cooper, Matthew A.; Naderer, Thomas; Traven, Ana

doi:10.1128/msphere.00074-16

Cited by 39 publications

(52 citation statements)

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“…We further demonstrated that inactivation of ERMES crippled the ability of C. albicans to evade innate immunity by macrophages, and further led to loss of fitness, particularly at host temperature of 37°C and particularly after long term, chronic inactivation of ERMES function in gene deletion mutants (Tucey et al, 2016 ). Genetic and cell biology data support the existence of an ERMES complex in C. albicans that is of equivalent composition as in S. cerevisiae , with four core subunits: Mmm1, Mdm10, Mdm34, and Mdm12 (Kornmann et al, 2009 ; Tucey et al, 2016 ). ERMES is conserved within fungi (Wideman et al, 2013 ), and a recent study of ERMES in the pathogenic mold Aspergillus fumigatus supports the idea that targeting ER-Mitochondria interactions might be promising as a therapeutic strategy against multiple, divergent pathogenic fungal species (Geißel et al, 2017 ).…”

Section: Introductionmentioning

confidence: 87%

“…They are also significant because during evolution ERMES has been lost in metazoans, and therefore no human homologs exist (Wideman et al, 2013 ), and in the human pathogenic yeast Candida albicans repression of MMM1 , the gene encoding the ER-anchored subunit of the ERMES, blocks virulence in mice infection (Becker et al, 2010 ). We recently performed the first detailed characterization of the ERMES complex in a human fungal pathogen, showing that the principal role of ERMES in C. albicans is to enable proper mitochondrial morphology (Tucey et al, 2016 ). We further demonstrated that inactivation of ERMES crippled the ability of C. albicans to evade innate immunity by macrophages, and further led to loss of fitness, particularly at host temperature of 37°C and particularly after long term, chronic inactivation of ERMES function in gene deletion mutants (Tucey et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…We recently performed the first detailed characterization of the ERMES complex in a human fungal pathogen, showing that the principal role of ERMES in C. albicans is to enable proper mitochondrial morphology (Tucey et al, 2016 ). We further demonstrated that inactivation of ERMES crippled the ability of C. albicans to evade innate immunity by macrophages, and further led to loss of fitness, particularly at host temperature of 37°C and particularly after long term, chronic inactivation of ERMES function in gene deletion mutants (Tucey et al, 2016 ). Genetic and cell biology data support the existence of an ERMES complex in C. albicans that is of equivalent composition as in S. cerevisiae , with four core subunits: Mmm1, Mdm10, Mdm34, and Mdm12 (Kornmann et al, 2009 ; Tucey et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Koch

Tucey

et al. 2017

Front. Microbiol.

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The interactions of mitochondria with the endoplasmic reticulum (ER) are crucial for maintaining proper mitochondrial morphology, function and dynamics. This enables cells to utilize their mitochondria optimally for energy production and anabolism, and it further provides for metabolic control over developmental decisions. In fungi, a key mechanism by which ER and mitochondria interact is via a membrane tether, the protein complex ERMES (ER-Mitochondria Encounter Structure). In the model yeast Saccharomyces cerevisiae, the mitochondrial GTPase Gem1 interacts with ERMES, and it has been proposed to regulate its activity. Here we report on the first characterization of Gem1 in a human fungal pathogen. We show that in Candida albicans Gem1 has a dominant role in ensuring proper mitochondrial morphology, and our data is consistent with Gem1 working with ERMES in this role. Mitochondrial respiration and steady state cellular phospholipid homeostasis are not impacted by inactivation of GEM1 in C. albicans. There are two major virulence-related consequences of disrupting mitochondrial morphology by GEM1 inactivation: C. albicans becomes hypersusceptible to cell wall stress, and is unable to grow invasively. In the gem1Δ/Δ mutant, it is specifically the invasive capacity of hyphae that is compromised, not the ability to transition from yeast to hyphal morphology, and this phenotype is shared with ERMES mutants. As a consequence of the hyphal invasion defect, the gem1Δ/Δ mutant is drastically hypovirulent in the worm infection model. Activation of the mitogen activated protein (MAP) kinase Cek1 is reduced in the gem1Δ/Δ mutant, and this function could explain both the susceptibility to cell wall stress and lack of invasive growth. This result establishes a new, respiration-independent mechanism of mitochondrial control over stress signaling and hyphal functions in C. albicans. We propose that ER-mitochondria interactions and the ER-Mitochondria Organizing Network (ERMIONE) play important roles in adaptive responses in fungi, in particular cell surface-related mechanisms that drive invasive growth and stress responsive behaviors that support fungal pathogenicity.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Koch

Tucey

et al. 2017

Front. Microbiol.

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“…More recently, Tucey et al (2016) characterized the C. albicans endoplasmic reticulum (ER)-mitochondria tether complex ERMES (mediator of interactions between organelles, providing membrane contact sites) and showed that the ERMES mmm1 mutant has a severely crippled ability to kill macrophages despite hyphal formation and normal phagocytosis and survival.…”

Section: Controlmentioning

confidence: 99%

Anti-Immune Strategies of Pathogenic Fungi

Marcos¹,

Oliveira²,

Melo³

et al. 2016

Front. Cell. Infect. Microbiol.

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Pathogenic fungi have developed many strategies to evade the host immune system. Multiple escape mechanisms appear to function together to inhibit attack by the various stages of both the adaptive and the innate immune response. Thus, after entering the host, such pathogens fight to overcome the immune system to allow their survival, colonization and spread to different sites of infection. Consequently, the establishment of a successful infectious process is closely related to the ability of the pathogen to modulate attack by the immune system. Most strategies employed to subvert or exploit the immune system are shared among different species of fungi. In this review, we summarize the main strategies employed for immune evasion by some of the major pathogenic fungi.

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“…Fission has been shown to isolate defective parts of the network and facilitate their turnover by mitophagy (Mao and Klionsky 2013). In recent years, much of the machinery governing fission and fusion has been elucidated (Pagliuso, Cossart and Stavru 2018), including important contributors such as interaction with the ER (Tucey et al 2016). As mitochondrial function is implicated in a wide variety of pathologies and stress responses, the study of mitochondrial morphology in pathogens such as C. albicans could be used to better understand the host-pathogen interaction.…”

Section: Introductionmentioning

confidence: 99%

An analysis of respiratory function and mitochondrial morphology in Candida albicans

Duvenage

Pentland

Munro

et al. 2019

Preprint

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Respiratory function and mitochondrial dynamics have been well characterised in a number of cell types, including the model yeast Saccharomyces cerevisiae, but remain under-researched in fungal pathogens such as Candida albicans. An understanding of mitochondrial activity and morphology is important if we are to understand the role that this organelle plays in adaption and response to stress. Here we examine the respiratory profiles of several prominent pathogenic Candida species and present a useful GFP probe for the study of mitochondrial morphology. We examine mitochondrial morphology under a variety of conditions that Candida species may encounter within the host, such as acidic pH, respiratory and oxidative stress. The GFP probe also allowed for the visualisation of mitochondria during hyphal development, during growth following macrophage engulfment and distribution within biofilms. These data demonstrate that the mitochondrial network of C. albicans is highly responsive to both environmental conditions and developmental cues, suggesting important roles for this organelle in environmental adaption.

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The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals

Cited by 39 publications

References 58 publications

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Anti-Immune Strategies of Pathogenic Fungi

An analysis of respiratory function and mitochondrial morphology in Candida albicans

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