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J. Biol. Chem., Vol. 278, Issue 45, 45011-45020, November 7, 2003

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The Effects of Drugs Inhibiting Protein Secretion in the Filamentous Fungus Trichoderma reesei

EVIDENCE FOR DOWN-REGULATION OF GENES THAT ENCODE SECRETED PROTEINS IN THE STRESSED CELLS^*

Tiina M. Pakula, Marjukka Laxell, Anne Huuskonen, Jaana Uusitalo, Markku Saloheimo, and Merja Penttilä

From the VTT Biotechnology, P. O. Box 1500, 02044 VTT, Espoo, Finland

To study the mechanisms of protein secretion as well as the cellular responses to impaired protein folding and transport in filamentous fungi, we have analyzed Trichoderma reesei cultures treated with chemical agents that interfere with these processes, dithiothreitol, brefeldin A, and the Ca²⁺-ionophore A23187. The effects of the drugs on the kinetics of protein synthesis and transport were characterized using metabolic labeling of synthesized proteins. Cellobiohydrolase I (CBHI, Cel7A), the major secreted cellulase, was analyzed as a model protein. Northern analysis showed that under conditions where protein transport was inhibited (treatments with dithiothreitol or brefeldin A) the unfolded protein response pathway was activated. The active form of the hac1 mRNA that mediates unfolded protein response signaling was induced, followed by induction of the foldase and chaperone genes pdi1 and bip1. Concomitant with the activation of the unfolded protein response pathway, the transcript levels of genes encoding secreted proteins, like cellulases and xylanases, were drastically decreased, suggesting a novel type of feedback mechanism activated in response to impairment in protein folding or transport (repression under secretion stress (RESS)). By studying expression of the reporter gene lacZ under cbh1 promoters of different length, it was shown that the feedback response was mediated through the cellulase promoter.

Received for publication, March 7, 2003 , and in revised form, August 25, 2003.

^* This work was supported by the European Union Biotechnology Program BIO4CT96-0535, the European Union V Framework Program Eurofung QLK3-CT-1999-00729, and the research program "VTT Industrial Biotechnology" (Academy of Finland, Finnish Centre of Excellence Program, 2000–2005, Project no. 64330). 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.

To whom correspondence should be addressed: VTT Biotechnology, P. O. Box 1500, 02044 VTT, Finland. Tel.: 358-9-456-78604; Fax: 358-9-455-2103; E-mail: tiina.pakula{at}vtt.fi.

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