H2O2 Induces Major Phosphorylation Changes in Critical Regulators of Signal Transduction, Gene Expression, Metabolism and Developmental Networks in Aspergillus nidulans

Carrasco-Navarro, Ulises; Aguirre, Jesús

doi:10.3390/jof7080624

Cited by 13 publications

(13 citation statements)

References 222 publications

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“…brlA and the other two genes in the central regulatory pathway ( abaA and wetA ) were also found to be regulated by SakA, a member of the stress-activated MAPK (SAPK) pathway in T. marneffei [ 77 ]. In a recent work analyzing the phosphoproteome response to H 2 O 2 in A. nidulans , Carrasco-Navarro and Aguirre [ 78 ] found that StuA, a protein required for proper expression of brlA , was specifically phosphorylated in the H 2 O 2 -condition, which suggests that phosphorylation plays also a role in the oxidative stress-mediated regulation of conidiation; interestingly, NapA was also phosphorylated in the H 2 O 2 -condition. In this work we describe for the first time a direct regulation of a gene in the conidiation central regulatory pathway, the brlA gene, by an oxidative stress defense protein; PcYap1 binds to a TTACTAA sequence in the brlA gene promoter and upregulates expression of this gene, thus triggering conidiation.…”

Section: Discussionmentioning

confidence: 99%

bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum

et al. 2022

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Background Reactive oxygen species (ROS) trigger different morphogenic processes in filamentous fungi and have been shown to play a role in the regulation of the biosynthesis of some secondary metabolites. Some bZIP transcription factors, such as Yap1, AtfA and AtfB, mediate resistance to oxidative stress and have a role in secondary metabolism regulation. In this work we aimed to get insight into the molecular basis of this regulation in the industrially important fungus Penicillium chrysogenum through the characterization of the role played by two effectors that mediate the oxidative stress response in development and secondary metabolism. Results In P. chrysogenum, penicillin biosynthesis and conidiation are stimulated by the addition of H2O2 to the culture medium, and this effect is mediated by the bZIP transcription factors PcYap1 and PcRsmA. Silencing of expression of both proteins by RNAi resulted in similar phenotypes, characterized by increased levels of ROS in the cell, reduced conidiation, higher sensitivity of conidia to H2O2 and a decrease in penicillin production. Both PcYap1 and PcRsmA are able to sense H2O2-generated ROS in vitro and change its conformation in response to this stimulus. PcYap1 and PcRsmA positively regulate the expression of brlA, the first gene of the conidiation central regulatory pathway. PcYap1 binds in vitro to a previously identified regulatory sequence in the promoter of the penicillin gene pcbAB: TTAGTAA, and to a TTACTAA sequence in the promoter of the brlA gene, whereas PcRsmA binds to the sequences TGAGACA and TTACGTAA (CRE motif) in the promoters of the pcbAB and penDE genes, respectively. Conclusions bZIP transcription factors PcYap1 and PcRsmA respond to the presence of H2O2-generated ROS and regulate oxidative stress response in the cell. Both proteins mediate ROS regulation of penicillin biosynthesis and conidiation by binding to specific regulatory elements in the promoters of key genes. PcYap1 is identified as the previously proposed transcription factor PTA1 (Penicillin Transcriptional Activator 1), which binds to the regulatory sequence TTAGTAA in the pcbAB gene promoter. This is the first report of a Yap1 protein directly regulating transcription of a secondary metabolism gene. A model describing the regulatory network mediated by PcYap1 and PcRsmA is proposed.

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Section: Discussionmentioning

confidence: 99%

bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum

et al. 2022

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“…The serine–threonine kinase is the target of rapamycin (TOR) and regulates cell growth and stress signalling in eukaryotes. A single TOR kinase TorA was characterized in A. nidulans , which contained four phosphosites during growth and three of them were dephosphorylated under oxidative stress (Carrasco‐Navarro and Aguirre, 2021). The TOR signalling pathway regulates phosphorylation of the Ser/Thr kinase Sch9, a substrate of TOR, to control fungal development and mediate multiple stresses responses as well as mycotoxin synthesis in some fungal pathogens (Gu et al ., 2015; Alves de Castro et al ., 2016).…”

Section: Post‐translational Regulation Of Secondary Metabolite Biosyn...mentioning

confidence: 99%

“…In A. nidulans , over 1964 proteins were characterized phosphorylated, among which the reversible phosphorylated state of 131 proteins were influenced by the oxidative stress agent hydrogen peroxide (H 2 O 2 ) (Carrasco‐Navarro and Aguirre, 2021). Additionally, the phosphorylation of critical components of MAPK, and TOR signalling as well as the proteins that involved in the regulation of primary and secondary metabolism were found affected by H 2 O 2 in A. nidulans .…”

Section: Post‐translational Regulation Of Secondary Metabolite Biosyn...mentioning

confidence: 99%

Post‐translational modifications drive secondary metabolite biosynthesis in Aspergillus: a review

Yang

Tian

Keller

2022

Environmental Microbiology

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Post-translational modifications (PTMs) are important for protein function and regulate multiple cellular processes and secondary metabolites (SMs) in fungi. Aspergillus species belong to a genus renown for an abundance of bioactive secondary metabolites, many important as toxins, pharmaceuticals and in industrial production. The genes required for secondary metabolites are typically co-localized in biosynthetic gene clusters (BGCs), which often localize in heterochromatic regions of genome and are 'turned off' under laboratory condition. Efforts have been made to 'turn on' these BGCs by genetic manipulation of histone modifications, which could convert the heterochromatic structure to euchromatin. Additionally, non-histone PTMs also play critical roles in the regulation of secondary metabolism. In this review, we collate the known roles of epigenetic and PTMs on Aspergillus SM production. We also summarize the proteomics approaches and bioinformatics tools for PTM identification and prediction and provide future perspectives on the emerging roles of PTM on regulation of SM biosynthesis in Aspergillus and other fungi.

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“…H 2 O 2 is considered to be the most relevant ROS in redox biology [ 10 ]. Indeed, in the fungus Aspergillus nidulans , H 2 O 2 activates the MAPKs SakA, MpkC [ 8 , 11 , 12 ], MpkA and MpkB [ 13 ], and changes the phosphorylation patterns of multiple other proteins involved in signal transduction, gene expression, metabolism and development [ 13 ]. SakA mediates the nuclear localization of its substrate SrkA, and when SakA is not present, H 2 O 2 induces SrkA mitochondrial localization [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

H2O2 Induces Calcium and ERMES Complex-Dependent Mitochondrial Constriction and Division as Well as Mitochondrial Outer Membrane Remodeling in Aspergillus nidulans

Garrido-Bazán

Aguirre

2022

JoF

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The dynamin-like protein DnmA and its receptor FisA are essential for H2O2-induced mitochondrial division in Aspergillus nidulans. Here, we show that in the absence of DnmA or FisA, mitochondria show few spontaneous transient constrictions, the frequency of which is extensively increased by H2O2 or the carbonyl cyanide m-chlorophenyl hydrazone (CCCP). While H2O2-induced constrictions are transient, CCCP induces a drastic and irreversible alteration of mitochondrial filaments. H2O2 induces a gradual mitochondrial depolarization, while CCCP-induced depolarization is abrupt. The calcium chelator BAPTA-AM prevents the formation of mitochondrial constrictions induced by either H2O2 or CCCP. H2O2 also induces major rearrangements of the mitochondrial outer membrane, which remain after constrictions dissipate, as well as changes in endoplasmic reticulum (ER) and nuclear morphology. Similar mitochondrial constriction, ER and nuclear morphology changes are detected during the early stages of asexual development. ER and ER-Mitochondria encounter structure (ERMES) complex—composed of proteins Mdm10, Mmm1, Mdm43 and Mdm12—are important for mitochondrial division in Saccharomyces cerevisiae. As the Mdm10 ortholog MdmB was found to be essential in A. nidulans, we evaluated its functions in ΔmdmB terminal mutants and ΔmdmB heterokaryons. ΔmdmB conidia produce a short germ tube that fails to grow further, in which inherited mitochondria become gigantic and round shaped, lacking clear contacts with the ER. In slow-growing ΔmdmB heterokaryotic mycelia, multiple hyphae contain very long mitochondria with high ROS levels, as occur in ΔdnmA and ΔfisA mutants. In this hyphae, H2O2 fails to induce mitochondrial constrictions but not outer mitochondrial membrane reshaping, indicating that these are two separate effects of H2O2. Our results indicate that H2O2 induces a generalized mitochondrial constriction response, prior to actual division, involving gradual depolarization; they also indicate that Ca2+ and the ERMES complex are critical for both mitochondrial constriction and division. This supports a view of mitochondrial dynamics as the result of a cascade of signaling events that can be initiated in vivo by H2O2.

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H2O2 Induces Major Phosphorylation Changes in Critical Regulators of Signal Transduction, Gene Expression, Metabolism and Developmental Networks in Aspergillus nidulans

Cited by 13 publications

References 222 publications

bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum

bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum

Post‐translational modifications drive secondary metabolite biosynthesis in Aspergillus: a review

H2O2 Induces Calcium and ERMES Complex-Dependent Mitochondrial Constriction and Division as Well as Mitochondrial Outer Membrane Remodeling in Aspergillus nidulans

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