The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence
Ries, Laure N. A.; Pardeshi, Lakhansing; Dong, Zhiqiang; Tan, Kaeling; Steenwyk, Jacob L.; Colabardini, Ana Cristina; Ferreira Filho, Jaire A.; Castro, Patricia A. de; Silva, Lilian P.; Preite, Nycolas W.; Almeida, Fausto; Assis, Leandro J. de; Santos, Renato A. C. dos; Bowyer, Paul; Bromley, Michael; Owens, Rebecca A.; Doyle, Sean; Demasi, Marilene ; Hernández, Diego C. R.; S. Netto, Luís Eduardo; Pupo, Monica T.; Rokas, Antonis; Loures, Flavio V.; Wong, Koon H.; Goldman, Gustavo H.
Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), which contribute to enhancing fungal fitness and growth within the mammalian host. Gliotoxin (GT) is a SM that interferes with the function and recruitment of innate immune cells, which are essential for eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and self-protection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT, by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important for virulence in a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA). Homologues of RglT and GliT are present in eurotiomycete and sordariomycete fungi, including the non-GT-producing fungus A. nidulans, where a conservation of function was described. Phylogenetically informed model testing led to an evolutionary scenario in which the GliT-based resistance mechanism is ancestral and RglT-mediated regulation of GliT occurred subsequently. In conclusion, this work describes the function of a previously uncharacterised TF in oxidative stress resistance, GT biosynthesis and self-protection in both GT-producing and non-producing Aspergillus species.
Ries LN.A., Pardeshi L, Dong Z, Tan K, Steenwyk JL., Colabardini AC, et al. The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence. PLoS. Pathog.. 2020 Jul;16(7):e1008645. doi:10.1371/journal.ppat.1008645.
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