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J. Biol. Chem., Vol. 279, Issue 48, 49762-49772, November 26, 2004

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Roles of O-Mannosylation of Aberrant Proteins in Reduction of the Load for Endoplasmic Reticulum Chaperones in Yeast^*

Kunio Nakatsukasa, Shigeo Okada, Kyohei Umebayashi¶, Ryoichi Fukuda||, Shuh-ichi Nishikawa, and Toshiya Endo**

From the Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan, the ^¶Department of Cell Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan, the ^||Department of Biotechnology, the University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan, ^**Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan, and the Institute for Advanced Research, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan

The protein quality control system in the endoplasmic reticulum (ER) ensures that only properly folded proteins are deployed throughout the cells. When nonnative proteins accumulate in the ER, the unfolded protein response is triggered to limit further accumulation of nonnative proteins and the ER is cleared of accumulated nonnative proteins by the ER-associated degradation (ERAD). In the yeast ER, aberrant nonnative proteins are mainly directed for the ERAD, but a distinct fraction of them instead receive O-mannosylation. In order to test whether O-mannosylation might also be a mechanism to process aberrant proteins in the ER, here we analyzed the effect of O-mannosylation on two kinds of model aberrant proteins, a series of N-glycosylation site mutants of prepro--factor and a pro-region-deleted derivative of Rhizopus niveus aspartic proteinase-I (pro) both in vitro and in vivo. O-Mannosylation increases solubilities of the aberrant proteins and renders them less dependent on the ER chaperone, BiP, for being soluble. The release from ER chaperones allows the aberrant proteins to exit out of the ER for the normal secretory pathway transport. When the gene for Pmt2p, responsible for the O-mannosylation of these aberrant proteins, and that for the ERAD were simultaneously deleted, the cell exhibited enhanced unfolded protein response. O-Mannosylation may therefore function as a fail-safe mechanism for the ERAD by solubilizing the aberrant proteins that overflowed from the ERAD pathway and reducing the load for ER chaperones.

Received for publication, March 23, 2004 , and in revised form, August 27, 2004.

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology and by a grant from the Japan Science and Technology Agency (to T. E.). 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.

A Research Fellow of the Japan Society for the Promotion of Science. Present address: Dept. of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260.

To whom correspondence should be addressed: Dept. of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Tel.: 81-52-789-2490; Fax: 81-52-789-2947; E-mail: endo{at}biochem.chem.nagoya-u.ac.jp.

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