Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA.
Secondary metabolites, including toxins and melanins, have been implicated as virulence attributes in invasive aspergillosis. Although not definitively proved, this supposition is supported by the decreased virulence of an Aspergillus fumigatus strain, DeltalaeA, that is crippled in the production of numerous secondary metabolites. However, loss of a single LaeA-regulated toxin, gliotoxin, did not recapitulate the hypovirulent DeltalaeA pathotype, thus implicating other toxins whose production is governed by LaeA. Toward this end, a whole-genome comparison of the transcriptional profile of wild-type, DeltalaeA, and complemented control strains showed that genes in 13 of 22 secondary metabolite gene clusters, including several A. fumigatus-specific mycotoxin clusters, were expressed at significantly lower levels in the DeltalaeA mutant. LaeA influences the expression of at least 9.5% of the genome (943 of 9,626 genes in A. fumigatus) but positively controls expression of 20% to 40% of major classes of secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs), polyketide synthases, and P450 monooxygenases. Tight regulation of NRPS-encoding genes was highlighted by quantitative real-time reverse-transcription PCR analysis. In addition, expression of a putative siderophore biosynthesis NRPS (NRPS2/sidE) was greatly reduced in the DeltalaeA mutant in comparison to controls under inducing iron-deficient conditions. Comparative genomic analysis showed that A. fumigatus secondary metabolite gene clusters constitute evolutionarily diverse regions that may be important for niche adaptation and virulence attributes. Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity.
Perrin
Robyn M
RM
Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Fedorova
Natalie D
ND
Bok
Jin Woo
JW
Cramer
Robert A
RA
Wortman
Jennifer R
JR
Kim
H Stanley
HS
Nierman
William C
WC
Keller
Nancy P
NP
D001232:Aspergillus fumigatus / Q000235:genetics*; D015825:Chromosomes, Fungal / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal / Q000235:genetics*; D014644:Genetic Variation; D023281:Genomics; D007501:Iron / Q000378:metabolism; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017262:Siderophores / Q000235:genetics*; D014158:Transcription, Genetic
D012331:RNA, Fungal; D012333:RNA, Messenger; D017262:Siderophores; D007501:Iron; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase