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Molecular and Cellular Biology, August 2009, p. 4067-4079, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01461-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

High-Affinity Transporters for NAD⁺ Precursors in Candida glabrata Are Regulated by Hst1 and Induced in Response to Niacin Limitation ^{, ,}

Biao Ma,^1, Shih-Jung Pan,¹ Renee Domergue,¹ Tracey Rigby,² Malcolm Whiteway,² David Johnson,³ and Brendan P. Cormack^1*

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,¹ Biotechnology Research Institute, National Research Council of Canada, Montréal, Québec H4P 2R2, Canada,² Research Service (151), VA Medical Center, Baltimore, Maryland 21201³

Received 17 September 2008/ Returned for modification 7 November 2008/ Accepted 12 May 2009

The yeast Candida glabrata is an opportunistic pathogen of humans. C. glabrata is a NAD⁺ auxotroph, and its growth depends on the availability of niacin (environmental vitamin precursors of NAD⁺). We have previously shown that a virulence-associated adhesin, encoded by EPA6, is transcriptionally induced in response to niacin limitation. Here we used transcript profiling to characterize the transcriptional response to niacin limitation and the roles of the sirtuins Hst1, Hst2, and Sir2 in mediating this response. The majority of genes transcriptionally induced by niacin limitation are regulated by Hst1, suggesting that it is the primary sensor of niacin limitation in C. glabrata. We show that three highly induced genes, TNA1, TNR1, and TNR2, encode transporters which are necessary and sufficient for high-affinity uptake of NAD⁺ precursors. Strikingly, if a tna1 tnr1 tnr2 mutant is starved for niacin, it exhibits an extended lag phase, suggesting a central role for the transporters in restoring NAD⁺ homeostasis after niacin limitation. Lastly, we had previously shown that the adhesin encoded by EPA6 is induced during experimental urinary tract infection (UTI); we show here that EPA6 transcriptional induction during UTI is strongly enhanced in the tna1 tnr1 tnr2 mutant strain, implicating the transporters in the growth of C. glabrata during infection.

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* Corresponding author. Mailing address: Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Hunterian 617, 725 North Wolfe Street, Baltimore, MD 21205-2185. Phone: (410) 614-4923. Fax: (410) 502-6718. E-mail: bcormack{at}jhmi.edu

Published ahead of print on 18 May 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

National Research Council of Canada publication NRC 50666.

Present address: The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.

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Molecular and Cellular Biology, August 2009, p. 4067-4079, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01461-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.