Identification and Characterization of Key Charged Residues in the Cofilin Protein Involved in Azole Susceptibility, Apoptosis, and Virulence of Aspergillus fumigatus

Lu, Zhongyi; Jia, Xiaodong; Chen, Yong; Han, Xiaonan; Chen, Fangyan; Tian, Shen; Su, Xueting; Li, Zongwei; Zhao, Jingya; Zhang, Xi; Hu, Mandong; Huang, Liuyu; Han, Li

doi:10.1128/aac.01659-17

Cited by 12 publications

(15 citation statements)

References 63 publications

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“…Taken together, these data extend the link between mitochondrial function and iron homeostasis to an effect on ergosterol biosynthesis ( Figure 3 ). Recently, a study has confirmed that mitochondrial dysfunction due to mutated cofilin affects ergosterol biosynthesis by regulating ergosterol biosynthesis gene ERG11 expression in A. fumigatus [ 44 ]. The mutated cofilin triggered fatty acid β-oxidation, which increased acetyl coenzyme A (acetyl-CoA) and ATP concentrations.…”

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

“…The mutated cofilin triggered fatty acid β-oxidation, which increased acetyl coenzyme A (acetyl-CoA) and ATP concentrations. The extra ATP supplies provided additional energy to drug efflux pumps, while excess acetyl-CoA induces overexpression of ERG11 gene ( Figure 3 ), affecting the ergosterol biosynthetic pathway and thus reducing susceptibility to azoles [ 44 ]. Taken together, the connection between mitochondrial function, ergosterol biosynthesis, and azole drug resistance is strong, but the mechanistic details are far from understood.…”

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

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Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

Song

Zhou

Zhang³

et al. 2020

Microorganisms

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In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.

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Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

Song

Zhou

Zhang³

et al. 2020

Microorganisms

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“…Besides, Xing et al (38) demonstrated that isoalantolactone inhibits IKKβ kinase activity and promotes apoptosis of glioblastoma cells by inducing translocation of cofilin-1 to the mitochondria and the release of mitochondrial cytochrome C to the cytoplasm, which activates caspase-3/9. In human leukemia cells, cofilin-1 translocation to the mitochondria could induce mitochondrial injury and cell apoptosis (39). Xiao et al (40) revealed that docetaxel induced apoptosis of prostate cancer cells by inhibiting cofilin-1 and paxillin signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

et al. 2020

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all-trans retinoic acid (aTra) and arsenic trioxide (as 2 o 3) are currently first-line treatments for acute promyelocytic leukemia (APL). However, a number of patients with APL are resistant to ATRA but still sensitive to As 2 o 3 , and the underlying mechanisms of this remain unclear. In the present study, two-dimensional gel electrophoresis, mass spectrometry and other proteomic methods were applied to screen and identify the differentially expressed proteins between the retinoic acid-sensitive cell lines and drug-resistant cell lines. The results demonstrated that in retinoic acid-resistant NB4-R1 cells, the protein expression of cofilin-1 was markedly increased compared with that in the drug-sensitive NB4 cells. Subsequently, the effects of cofilin-1 on As 2 o 3-induced apoptosis in NB4-R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As 2 o 3-treated nB4-r1 cells, with increased expression levels of cleaved-poly (ADP-ribose) polymerase and cleaved-caspase 12. Cofilin-1 expression was significantly decreased at both the mRNA and protein levels in the As 2 o 3-treated group compared with the control. Western blotting further revealed that As 2 o 3 treatment decreased the cytoplasmic cofilin-1 level but increased its expression in the mitochondrion. However, the opposite effects of As 2 o 3 on the cytochrome C distribution were found in NB4-R1 cells. This suggested that As 2 o 3 can induce the transfer of cofilin-1 from the cytoplasm to mitochondria and trigger the release of mitochondrial cytochrome C in NB4-R1 cells. Moreover, cofilin-1 knockdown by its specific short hairpin RNA significantly suppressed As 2 o 3-induced NB4-R1 cell apoptosis and inhibited the release of mitochondrial cytochrome C. Whereas, overexpression of cofilin-1 using a plasmid vector carrying cofilin-1 increased the release of cytochrome C into the cytoplasm from the mitochondria in As 2 o 3-treated nB4-r1 cells. In conclusion, cofilin-1 played a role in As 2 o 3-induced NB4-R1 cell apoptosis and it might be a novel target for APL treatment.

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“…It was interesting that cofilin expression was correlated with the alteration of cell wall composition of A. fumigatus , which might be a contributor to the lower internalization and inflammatory response in host cells ( Bertuzzi et al, 2014 ; Lu et al, 2018 ). However, some other reasons for this lower internalization and less inflammatory response of cofilin teton mutant could not be excluded.…”

Section: Discussionmentioning

confidence: 99%

Role of Downregulation and Phosphorylation of Cofilin in Polarized Growth, MpkA Activation and Stress Response of Aspergillus fumigatus

Jia

Zhang

et al. 2018

Front. Microbiol.

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Aspergillus fumigatus causes most of aspergillosis in clinic and comprehensive function analysis of its key protein would promote anti-aspergillosis. In a previous study, we speculated actin depolymerizing factor cofilin might be essential for A. fumigatus viability and found its overexpression upregulated oxidative response and cell wall polysaccharide synthesis of this pathogen. Here, we constructed a conditional cofilin mutant to determine the essential role of cofilin. And the role of cofilin downregulation and phosphorylation in A. fumigatus was further analyzed. Cofilin was required for the polarized growth and heat sensitivity of A. fumigatus. Downregulation of cofilin caused hyphal cytoplasmic leakage, increased the sensitivity of A. fumigatus to sodium dodecyl sulfonate but not to calcofluor white and Congo Red and farnesol, and enhanced the basal phosphorylation level of MpkA, suggesting that cofilin affected the cell wall integrity (CWI) signaling. Downregulation of cofilin also increased the sensitivity of A. fumigatus to alkaline pH and H2O2. Repressing cofilin expression in A. fumigatus lead to attenuated virulence, which manifested as lower adherence and internalization rates, weaker host inflammatory response and shorter survival rate in a Galleria mellonella model. Expression of non-phosphorylated cofilin with a mutation of S5A had little impacts on A. fumigatus, whereas expression of a mimic-phosphorylated cofilin with a mutation of S5E resulted in inhibited growth, increased phospho-MpkA level, and decreased pathogenicity. In conclusion, cofilin is crucial to modulating the polarized growth, stress response, CWI and virulence of A. fumigatus.

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Identification and Characterization of Key Charged Residues in the Cofilin Protein Involved in Azole Susceptibility, Apoptosis, and Virulence of Aspergillus fumigatus

Cited by 12 publications

References 63 publications

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

Role of Downregulation and Phosphorylation of Cofilin in Polarized Growth, MpkA Activation and Stress Response of Aspergillus fumigatus

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