tailieunhanh - Báo cáo khoa học: Endoplasmic reticulum stress caused by aggregate-prone proteins containing homopolymeric amino acids

Many human proteins have homopolymeric amino acid (HPAA) tracts, but their physiological functions or cellular effects are not well understood. Previously, we expressed 20 HPAAs in mammalian cells and showed char-acteristic intracellular localization, in that hydrophobic HPAAs aggregated strongly and caused high cytotoxicity in proportion to their hydrophobic-ity. | ỊFEBS Journal Endoplasmic reticulum stress caused by aggregate-prone proteins containing homopolymeric amino acids Naohiro Uchio1 Yoko Oma1 Kazuya Toriumi1 Noboru Sasagawa1 Isei Tanida2 Eriko Fujita3 Yoriko Kouroku3 Reiko Kuroda1 Takashi Momoi3 and Shoichi Ishiura1 1 Department of Life Sciences Graduate Schoolof Arts and Sciences The University of Tokyo Japan 2 Department of Biochemistry Juntendo University Schoolof Medicine Tokyo Japan 3 Division of Development and Differentiation NationalInstitute of Neuroscience NCNP Kodaira Tokyo Japan Keywords ER stress polyglutamine proteasome protein aggregation ubiquitin Correspondence S. Ishiura Department of Life Sciences Graduate School of Arts and Sciences The University of Tokyo 3-8-1 Komaba Meguro-Ku Tokyo 153-8902 Japan Fax 81 35454 6739 Tel 81 35454 6739 E-mail cishiura@ Received 2 May 2007 revised 1 August 2007 accepted 3 September 2007 doi Many human proteins have homopolymeric amino acid HPAA tracts but their physiological functions or cellular effects are not well understood. Previously we expressed 20 HPAAs in mammalian cells and showed characteristic intracellular localization in that hydrophobic HPAAs aggregated strongly and caused high cytotoxicity in proportion to their hydrophobicity. In the present study we investigated the cytotoxicity of these aggregate-prone hydrophobic HPAAs assuming that the ubiquitin proteasome system is impaired in the same manner as other well-known aggregate-prone polyglutamine-containing proteins. Some highly hydrophobic HPAAs caused a deficiency in the ubiquitin proteasome system and excess endoplasmic reticulum stress leading to apoptosis. These results indicate that the property of causing excess endoplasmic reticulum stress by protea-some impairment may contribute to the strong cytotoxicity of highly hydrophobic HPAAs and proteasome impairment and the resulting excess endoplasmic reticulum stress is not a common .