アクティブボード・２００９年　６月
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研究発表を行った学会；
・The Kumamoto University Global COE International Joint Symposium on Cell Fate Regulation Research: Molecular Basis and Therapeutic Potentials.
　２００９年　４月　９日〜１０日（熊本）

タイトル；BiP negatively regulates the endoplasmic reticulum-associated degradation of transthyretin variants in mammalian cells.
　
発表者；　佐藤　卓史　氏
　　　（熊本大学　大学院医学薬学研究部　遺伝子機能応用学分野）
Abstract；
　Amyloid fibril formation of mutant transthyretin (TTR) that causes familial amyloid polyneuropathy occurs in the extracellular space. Thus, secretion of TTR variants contributes to the pathogenesis of amyloidosis. However, the molecular mechanisms underlying the endoplasmic reticulum (ER) exit or retention and subsequent degradation of TTR variants remain unclear. Here, we demonstrated that the non-secreted TTR variants such as D18G TTR and amyloidogenic TTRs with introduced monomeric mutation (M-TTRs) stably interact with the ER chaperone BiP in mammalian cells. These proteins were co-secreted with the secreted form of BiP in which the KDEL signal was removed, indicating that BiP partially contributes to the ER retention of non-secreted TTR variants. More interestingly, the degradation efficiency of non-secreted TTRs was increased when BiP was down-regulated by siRNA. Thus, BiP protects the TTR variants from immediate degradation. Additionally, we showed that the stability of non-secreted TTR variants is not disturbed in the coat complex II (COPII)-deficient conditions, which are enough to inhibit the ER export of secreted TTR variants including wild-type TTR. Therefore, the post-ER retrieval mechanism might not contribute to the ER-associated degradation (ERAD) of non-secreted TTR variants. These findings suggest that the affinity to the ER-resident protein BiP regulates the fate of TTR variants in the ER.