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 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 proteasome 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 cytotoxic effect of aggregate-prone proteins such as polyglutamine.
Uchio
Naohiro
N
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan.
Oma
Yoko
Y
Toriumi
Kazuya
K
Sasagawa
Noboru
N
Tanida
Isei
I
Fujita
Eriko
E
Kouroku
Yoriko
Y
Kuroda
Reiko
R
Momoi
Takashi
T
Ishiura
Shoichi
S
D000596:Amino Acids / Q000032:analysis / Q000737:chemistry*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology*; D057927:Hydrophobic and Hydrophilic Interactions; D007930:Leucine / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D000596:Amino Acids; D001426:Bacterial Proteins; D008164:Luminescent Proteins; D010455:Peptides; D025801:Ubiquitin; C054562:yellow fluorescent protein, Bacteria; C097188:polyglutamine; C043801:polyisoleucine; D046988:Proteasome Endopeptidase Complex; D007930:Leucine