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Antimicrob Agents Chemother. 2018 Apr 26;62(5). pii: e01659-17. doi: 10.1128/AAC.01659-17. Print 2018 May.

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

Lu Z1,2, Jia X2,3, Chen Y2, Han X2, Chen F2, Tian S2, Su X2, Li Z2, Zhao J2, Zhang X1,2, Hu M1,2, Huang L4,2, Han L4,2.

Author information

1
Academy of Military Medical Sciences, Academy of Military Sciences, PLA, Beijing, China.
2
Institute for Disease Control and Prevention of PLA, Beijing, China.
3
Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing, China.
4
Academy of Military Medical Sciences, Academy of Military Sciences, PLA, Beijing, China huangliuyuly@163.com hanlicdc@163.com.

Abstract

Through some specific amino acid residues, cofilin, a ubiquitous actin depolymerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae; however, this modulation in a major fungal pathogen, Aspergillus fumigatus, was still unclear. Hereby, it was found, first, that mutations on several charged residues in cofilin to alanine, D19A-R21A, E48A, and K36A, increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks, including mitochondrial membrane potential depolarization, cytochrome c release, upregulation of metacaspases, and DNA cleavage, in A. fumigatus Two of these mutations (D19A-R21A and K36A) increased acetyl coenzyme A and ATP concentrations by triggering fatty acid β-oxidation. The upregulated acetyl coenzyme A affected the ergosterol biosynthetic pathway, leading to overexpression of cyp51A and -B, while excess ATP fueled ATP-binding cassette transporters. Besides, both of these mutations reduced the susceptibility of A. fumigatus to azole drugs and enhanced the virulence of A. fumigatus in a Galleria mellonella infection model. Taken together, novel and key charged residues in cofilin were identified to be essential modules regulating the mitochondrial function involved in azole susceptibility, apoptosis, and virulence of A. fumigatus.

KEYWORDS:

Aspergillus fumigatus; apoptosis; azole susceptibility; cofilin; mitochondria; virulence

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