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Originally published In Press as doi:10.1074/jbc.M105829200 on August 28, 2001

J. Biol. Chem., Vol. 276, Issue 44, 41444-41454, November 2, 2001
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Activation of the Ras-cAMP Signal Transduction Pathway Inhibits the Proteasome-independent Degradation of Misfolded Protein Aggregates in the Endoplasmic Reticulum Lumen*

Kyohei UmebayashiDagger §, Ryouichi FukudaDagger , Aiko Hirata, Hiroyuki HoriuchiDagger , Akihiko Nakano||, Akinori OhtaDagger , and Masamichi TakagiDagger

From the Dagger  Department of Biotechnology and  Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-8657 and the || Molecular Membrane Biology Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Many kinds of misfolded secretory proteins are known to be degraded in the endoplasmic reticulum (ER). Dislocation of misfolded proteins from the ER to the cytosol and subsequent degradation by the proteasome have been demonstrated. Using the yeast Saccharomyces cerevisiae, we have been studying the secretion of a heterologous protein, Rhizopus niveus aspartic proteinase-I (RNAP-I). Previously, we found that the pro sequence of RNAP-I is important for the folding and secretion, and that Delta pro, a mutated derivative of RNAP-I in which the entire region of the pro sequence is deleted, forms gross aggregates in the yeast ER. In this study, we show that the degradation of Delta pro occurs independently of the proteasome. Its degradation was not inhibited either by a potent proteasome inhibitor or in a proteasome mutant. We also show that neither the export from the ER nor the vacuolar proteinase is required for the degradation of Delta pro. These results raise the possibility that the Delta pro aggregates are degraded in the ER lumen. We have isolated a yeast mutant in which the degradation of Delta pro is delayed. We show that the mutated gene is IRA2, which encodes a GTPase-activating protein for Ras. Because Ira2 protein is a negative regulator of the Ras-cAMP pathway, this result suggests that hyperactivation of the Ras-cAMP pathway inhibits the degradation of Delta pro. Consistently, down-regulation of the Ras-cAMP pathway in the ira2 mutant suppressed the defect of the degradation of Delta pro. Thus, the Ras-cAMP signal transduction pathway seems to control the proteasome-independent degradation of the ER misfolded protein aggregates.

* This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan. This work was partly performed using the facilities of the Biotechnology Research Center, The University of Tokyo.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists and a Special Postdoctoral Researcher at RIKEN. To whom correspondence should be addressed (present address): Molecular Membrane Biology Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel.: 81-48-467-9548; Fax: 81-48-462-4679; E-mail: kyohei@postman.riken.go.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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