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J. Biol. Chem., Vol. 282, Issue 45, 32935-32948, November 9, 2007

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Survival in the Presence of Antifungals

GENOME-WIDE EXPRESSION PROFILING OF ASPERGILLUS NIGER IN RESPONSE TO SUBLETHAL CONCENTRATIONS OF CASPOFUNGIN AND FENPROPIMORPH^*

Vera Meyer¹, Robbert A. Damveld², Mark Arentshorst, Ulf Stahl, Cees A. M. J. J. van den Hondel, and Arthur F. J. Ram

From the Department of Microbiology and Genetics, Institute of Biotechnology, Berlin University of Technology, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany and the Department of Molecular Microbiology, Institute of Biology, Leiden University, Wassenaarseweg 64, 2333 AL Leiden, The Netherlands

How yeast cells respond to cell wall stress is relatively well understood; however, how filamentous fungi cope with cell wall damage is largely unexplored. Here we report the first transcriptome analysis of Aspergillus niger exposed to the antifungal compounds caspofungin, an inhibitor of -1,3-glucan synthesis, and fenpropimorph, which inhibits ergosterol synthesis. The presence of sublethal drug concentrations allowed A. niger to adapt to the stress conditions and to continue growth by the establishment of new polarity axes and formation of new germ tubes. By comparing the expression profile between caspofungin-exposed and nonexposed A. niger germlings, we identified a total of 172 responsive genes out of 14,509 open reading frames present on the Affymetrix microarray chips. Among 165 up-regulated genes, mainly genes predicted to function in (i) cell wall assembly and remodeling, (ii) cytoskeletal organization, (iii) signaling, and (iv) oxidative stress response were affected. Fenpropimorph modulated expression of 43 genes, of which 41 showed enhanced expression. Here, genes predicted to function in (i) membrane reconstruction, (ii) lipid signaling, (iii) cell wall remodeling, and (iv) oxidative stress response were identified. Northern analyses of selected genes were used to confirm the microarray analyses. The results further show that expression of the agsA gene encoding an -1,3-glucan synthase is up-regulated by both compounds. Using two PagsA-GFP reporter strains of A. niger and subjecting them to 16 different antifungal compounds, including caspofungin and fenpropimorph, we could show that agsA is specifically activated by compounds interfering directly or indirectly with cell wall biosynthesis.

Received for publication, July 17, 2007 , and in revised form, August 29, 2007.

^* The work performed at the Kluyver Centre for Genomics of Industrial Fermentation was supported by the Netherlands Genomics Initiative and by a grant from the Dutch Foundation for Technical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

² Present address: DSM Food Specialties, A. Fleminglaan 1, 2600 MA Delft, The Netherlands.

¹ To whom correspondence should be addressed. Tel.: 49-30-31472827; Fax: 49-30-31472922; E-mail: v.meyer{at}lb.tu-berlin.de.

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