The virulence of the opportunistic fungal pathogen<i>Aspergillus fumigatus</i>requires cooperation between the endoplasmic reticulum-associated degradation pathway (ERAD) and the unfolded protein response (UPR)

Richie, Daryl L.; Feng, Xizhi; Hartl, Lukas; Aimanianda, Vishukumar; Krishnan, Karthik; Powers-Fletcher, Margaret V.; Watson, Douglas S.; Galande, Amit K.; White, Stephanie M.; Willett, Taryn; Latgé, Jean‐Paul; Rhodes, Judith C.; Askew, David

doi:10.4161/viru.2.1.13345

Cited by 45 publications

(38 citation statements)

References 41 publications

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“…7). The ⌬derA mutant did not show this decrease, consistent with a previous study on this strain (7). In contrast, the ⌬hrdA ⌬derA mutant showed a 90% reduction in …”

Section: Resultssupporting

confidence: 77%

“…5), suggesting a role for HrdA in the well-known thermotolerance of the fungus (31). As previously reported, the ⌬derA mutant did not show this increase in thermosensitivity (7). Moreover, the ⌬hrdA ⌬derA mutant showed no further increase in temperature sensitivity relative to the ⌬hrdA mutant, suggesting that HrdA function is more vital to thermotolerance than DerA function.…”

Section: Resultssupporting

confidence: 57%

“…An emerging body of evidence suggests that the secretory pathway of filamentous fungi is a point of vulnerability that could be accessible to therapeutic intervention (6,7). The genome of A. fumigatus, like those of many other environmental saprophytic fungi, is enriched for secreted hydrolytic enzymes.…”

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confidence: 99%

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Effects of a Defective Endoplasmic Reticulum-Associated Degradation Pathway on the Stress Response, Virulence, and Antifungal Drug Susceptibility of the Mold Pathogen Aspergillus fumigatus

et al. 2013

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Proteins that are destined for release outside the eukaryotic cell, insertion into the plasma membrane, or delivery to intracellular organelles are processed and folded in the endoplasmic reticulum (ER). An imbalance between the level of nascent proteins entering the ER and the organelle's ability to manage that load results in the accumulation of unfolded proteins. Terminally unfolded proteins are disposed of by ER-associated degradation (ERAD), a pathway that transports the aberrant proteins across the ER membrane into the cytosol for proteasomal degradation. The ERAD pathway was targeted in the mold pathogen Aspergillus fumigatus by deleting the hrdA gene, encoding the A. fumigatus ortholog of Hrd1, the E3 ubiquitin ligase previously shown to contribute to ERAD in other species. Loss of HrdA was associated with impaired degradation of a folding-defective ERAD substrate, CPY*, as well as activation of the unfolded-protein response (UPR). The ⌬hrdA mutant showed resistance to voriconazole and reduced thermotolerance but was otherwise unaffected by a variety of environmental stressors. A double-deletion mutant deficient in both HrdA and another component of the same ERAD complex, DerA, was defective in secretion and showed hypersensitivity to ER, thermal, and cell wall stress. However, the ⌬hrdA ⌬derA mutant remained virulent in mouse and insect infection models. These data demonstrate that HrdA and DerA support complementary ERAD functions that promote survival under conditions of ER stress but are dispensable for virulence in the host environment.

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“…7). The ⌬derA mutant did not show this decrease, consistent with a previous study on this strain (7). In contrast, the ⌬hrdA ⌬derA mutant showed a 90% reduction in …”

Section: Resultssupporting

confidence: 77%

Section: Resultssupporting

confidence: 57%

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Effects of a Defective Endoplasmic Reticulum-Associated Degradation Pathway on the Stress Response, Virulence, and Antifungal Drug Susceptibility of the Mold Pathogen Aspergillus fumigatus

et al. 2013

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“…DscB contains 3 transmembrane domains, a signal peptide, and a conserved domain in the Rhomboid-like superfamily. Dsc2 and DscB both contain sequence similarity with the Der1 family of proteins, which are involved in ER-associated degradation (ERAD) and have recently been associated with virulence in A. fumigatus (39). S. pombe Dsc3 was most similar to A. fumigatus AFUB_067780 (DscC).…”

Section: Identification Of Putative Dsc Orthologs Inmentioning

confidence: 95%

Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

et al. 2012

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Hypoxia is an environmental stress encountered by Aspergillus fumigatus during invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA, dscB, dscC, and dscD, here referred to as dscA-D) with previously unknown functions in A. fumigatus that are orthologs of the Schizosaccharomyces pombe genes dsc1, dsc2, dsc3, and dsc4 (dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. A. fumigatus null dscA-D mutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes in S. pombe, both ⌬dscA and ⌬dscC resulted in reduced cleavage of the SrbA precursor protein in A. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ⌬dscA and ⌬dscC strains revealed that these genes are critical for A. fumigatus virulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ⌬dscA strain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes in A. fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.A s mortality due to invasive fungal infections (IFIs) continues to remain high despite improved diagnostics and prophylactic use of antifungal drugs, research to better understand fungal pathogenesis mechanisms is important. The aim of this research is to uncover new aspects of fungal physiology or the fungus-host interaction that can be manipulated to improve treatment outcomes. Investigating the host microenvironments encountered by human-pathogenic fungi during the initiation, development, and active stages of subsequent infection and how fungi adapt to these dynamic environments is one area where potential therapeutic opportunities exist.Recently, there has been an increased interest in how levels of oxygen at the site of infection impact the outcome of IFIs (18, 22). A major reason for this interest is that fungal strains with a deficient ability to adapt to hypoxia fail to cause lethal disease in murine models. Among the best examples of these fungal strains are the Cryptococcus neoformans and Aspergillus fumigatus null mutants of the sterol regulatory element-binding proteins (SREBP) (Sre1 and SrbA, respectively) (11,12,46). SREBPs were first identified in higher eukaryotes as regulators of cholesterol and lipid metabolism (7,19,20,37,45). Mammalian SREBPs are synthesized as endoplasmic reticulum (ER) membrane-bound precursors and contain...

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“…However, upregulation of ERAD activity by the UPR is needed when the level of unfolded proteins reaches a critical threshold of toxicity. The connection between these pathways is also evident in A. fumigatus, in which mutants deficient in both the UPR and ERAD are less fit than those lacking the UPR or ERAD alone (52).…”

Section: Discussionmentioning

confidence: 90%

The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

Raj

Krishnan

Askew

et al. 2016

Antimicrob Agents Chemother

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iIn a search for new antifungal compounds, we screened a library of 4,454 chemicals for toxicity against the human fungal pathogen Aspergillus fumigatus. We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungi A. fumigatus, Cryptococcus neoformans, Candida albicans, and Saccharomyces cerevisiae but lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885 S. cerevisiae mutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in both S. cerevisiae and A. fumigatus, indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR in A. fumigatus and UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.

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The virulence of the opportunistic fungal pathogenAspergillus fumigatusrequires cooperation between the endoplasmic reticulum-associated degradation pathway (ERAD) and the unfolded protein response (UPR)

Abstract: Askew (2011) The virulence of the opportunistic fungal pathogen Aspergillusfumigatus requires cooperation between the endoplasmic reticulum-associated degradation pathway (ERAD) and the unfolded protein response (UPR), Virulence, 2:1, 12-21,

Cited by 45 publications

References 41 publications

Effects of a Defective Endoplasmic Reticulum-Associated Degradation Pathway on the Stress Response, Virulence, and Antifungal Drug Susceptibility of the Mold Pathogen Aspergillus fumigatus

Effects of a Defective Endoplasmic Reticulum-Associated Degradation Pathway on the Stress Response, Virulence, and Antifungal Drug Susceptibility of the Mold Pathogen Aspergillus fumigatus

Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

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