The novel globin protein fungoglobin is involved in low oxygen adaptation of <scp><i>A</i></scp><i>spergillus fumigatus</i>

Hillmann, Falk; Linde, Jörg; Beckmann, Nicola; Cyrulies, Michael; Straßburger, Maria; Heinekamp, Thorsten; Haas, Hubertus; Guthke, Reinhard; Kniemeyer, Olaf; Brakhage, Axel A.

doi:10.1111/mmi.12679

Cited by 21 publications

(27 citation statements)

References 60 publications

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“…At present, genome-wide transcriptional profiling data of the hypoxic stress response are available from several filamentous ascomycetes: A. nidulans, A. oryzae, A. fumigatus, and Trichoderma reesei (Barker et al 2012;Bonaccorsi et al 2006;Hillmann et al 2014;Kroll et al 2014;Losada et al 2014;Masuo et al 2010;Terabayashi et al 2012). A somewhat smaller number of studies have been published on proteomic changes of A. nidulans and A. fumigatus during adaptation to low oxygen partial pressures (Barker et al 2012;Shimizu et al 2009;Vödisch et al 2011).…”

Section: Gene and Protein Expression During Hypoxiamentioning

confidence: 98%

“…Several authors have reported that sustained mycelial growth of A. fumigatus requires O 2 levels around 0.1-0.2 % (Grahl et al , 2012bHall and Denning 1994;Hillmann et al 2014). Intriguingly, even fungi like the fermentative brewer's yeast Saccharomyces cerevisiae depend at least on some trace amounts of O 2 as substrate in anabolic pathways for the biosynthesis of sterols and unsaturated fatty acids (Rosenfeld et al 2003;Visser et al 1990).…”

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confidence: 94%

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Insights into the cellular responses to hypoxia in filamentous fungi

2015

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Most eukaryotes require molecular oxygen for growth. In general, oxygen is the terminal electron acceptor of the respiratory chain and represents an important substrate for the biosynthesis of cellular compounds. However, in their natural environment, such as soil, and also during the infection, filamentous fungi are confronted with low levels of atmospheric oxygen. Transcriptome and proteome studies on the hypoxic response of filamentous fungi revealed significant alteration of the gene expression and protein synthesis upon hypoxia. These analyses discovered not only common but also species-specific responses to hypoxia with regard to NAD(+) regeneration systems and other metabolic pathways. A surprising outcome was that the induction of oxidative and nitrosative stress defenses during oxygen limitation represents a general trait of adaptation to hypoxia in many fungi. The interplay of these different stress responses is poorly understood, but recent studies have shown that adaptation to hypoxia contributes to virulence of pathogenic fungi. In this review, results on metabolic changes of filamentous fungi during adaptation to hypoxia are summarized and discussed.

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Section: Gene and Protein Expression During Hypoxiamentioning

confidence: 98%

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confidence: 94%

Insights into the cellular responses to hypoxia in filamentous fungi

2015

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“…Such levels of hypoxia are normally no threat for many aspergilli, as trace oxygen levels are often sufficient to support their growth. To sustain electron flow during such conditions, A. fumigatus finetunes components of its respiratory machinery (7)(8)(9)(10). Enzymatic steps requiring molecular O 2 in heme or ergosterol biosynthesis are highly sensitive to hypoxia and are under the control of the sterol regulatory element binding proteins (SREBPs) SrbA and SrbB.…”

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confidence: 99%

“…Primers used for DNA amplification and DIG (digoxigenin) labeling of gene-specific probes are listed in Table S2 in the supplemental material. Semidry blotting, hybridization, and fluorescence-based detection were all performed as described previously (9).…”

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Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence

et al. 2016

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dAspergillus fumigatus is the most common pathogenic mold infecting humans and a significant cause of morbidity and mortality in immunocompromised patients. In invasive pulmonary aspergillosis, A. fumigatus spores are inhaled into the lungs, undergoing germination and invasive hyphal growth. The fungus occludes and disrupts the blood vessels, leading to hypoxia and eventual tissue necrosis. The ability of this mold to adapt to hypoxia is regulated in part by the sterol regulatory element binding protein (SREBP) SrbA and the DscA to DscD Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. Loss of the genes encoding these proteins results in avirulence. To identify novel regulators of hypoxia sensing, we screened the Neurospora crassa gene deletion library under hypoxia and identified a novel rhomboid family protease essential for hypoxic growth. Deletion of the A. fumigatus rhomboid homolog rbdA resulted in an inability to grow under hypoxia, hypersensitivity to CoCl 2 , nikkomycin Z, fluconazole, and ferrozine, abnormal swollen tip morphology, and transcriptional dysregulation-accurately phenocopying deletion of srbA. In vivo, rbdA deletion resulted in increased sensitivity to phagocytic killing, a reduced inflammatory Th1 and Th17 response, and strongly attenuated virulence. Phenotypic rescue of the ⌬rbdA mutant was achieved by expression and nuclear localization of the N terminus of SrbA, including its HLH domain, further indicating that RbdA and SrbA act in the same signaling pathway. In summary, we have identified RbdA, a novel putative rhomboid family protease in A. fumigatus that mediates hypoxia adaptation and fungal virulence and that is likely linked to SrbA cleavage and activation.T he filamentous fungus Aspergillus fumigatus grows as an environmental saprophyte but can infect humans and animals through its dispersed asexual conidia. Upon inhalation by an immunocompromised host, conidia can germinate to form hyphae which infiltrate the surrounding lung tissue, causing often fatal invasive aspergillosis (IA). It is estimated that worldwide, more than 200,000 individuals suffer from life-threatening IA, with mortality rates ranging between 30 to 95% (1). These alarming statistics are a result of the generally poor health status of the patients, limited diagnostic and therapeutic options, and the arsenal of virulence-promoting properties of this ubiquitous mold (2, 3). Besides the abilities of the fungus to produce potent mycotoxins and to escape from the host innate immune cells, thermophilic growth and versatile nutrient acquisition are further general physiological attributes which favor growth on decaying matter as well as in the human host (4, 5). Adaptation to O 2 concentrations below normal atmospheric levels of 21% is an additional challenge that A. fumigatus must cope with during colonization. O 2 levels can drop to 2 to 4% on the surface of healthy alveolar tissue and be further diminished to less than 1% upon inflammation (6). Such levels of hypoxia are normally no th...

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“…1). None of the transcriptomic data, taken from various growth conditions, indicated any transcription of ftpA or of other ftp cluster genes (19)(20)(21). Therefore, we could not a priori exclude a pseudogene scenario.…”

Section: Resultsmentioning

confidence: 99%

Genetic Engineering Activates Biosynthesis of Aromatic Fumaric Acid Amides in the Human Pathogen Aspergillus fumigatus

Kalb

Heinekamp

Lackner

et al. 2015

Appl Environ Microbiol

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The Aspergillus fumigatus nonribosomal peptide synthetase FtpA is among the few of this species whose natural product has remained unknown. Both FtpA adenylation domains were characterized in vitro. Fumaric acid was identified as preferred substrate of the first and both L-tyrosine and L-phenylalanine as preferred substrates of the second adenylation domain. Genetically engineered A. fumigatus strains expressed either ftpA or the regulator gene ftpR, encoded in the same cluster of genes, under the control of the doxycycline-inducible tetracycline-induced transcriptional activation (tet-on) cassette. These strains produced fumaryl-L-tyrosine and fumaryl-L-phenylalanine which were identified by liquid chromatography and high-resolution mass spectrometry. Modeling of the first adenylation domain in silico provided insight into the structural requirements to bind fumaric acid as peptide synthetase substrate. This work adds aromatic fumaric acid amides to the secondary metabolome of the important human pathogen A. fumigatus which was previously not known as a producer of these compounds.

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The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

Cited by 21 publications

References 60 publications

Insights into the cellular responses to hypoxia in filamentous fungi

Insights into the cellular responses to hypoxia in filamentous fungi

Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence

Genetic Engineering Activates Biosynthesis of Aromatic Fumaric Acid Amides in the Human Pathogen Aspergillus fumigatus

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