The Endoplasmic Reticulum-associated Degradation of Transthyretin Variants Is Negatively Regulated by BiP in Mammalian Cells*
The Endoplasmic Reticulum-associated Degradation of Transthyretin Variants Is Negatively Regulated by BiP in Mammalian Cells*
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DOI：
10.1074/jbc.m809354200
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发表时间：
2009-03
影响因子：
4.8
通讯作者：
S. Susuki;Takashi Sato;M. Miyata;Mamiko Momohara;M. Suico;T. Shuto;Y. Ando;H. Kai
中科院分区：
文献类型：
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作者：
S. Susuki;Takashi Sato;M. Miyata;Mamiko Momohara;M. Suico;T. Shuto;Y. Ando;H. Kai
引起家族性淀粉样多神经病变的突变型甲状腺素（TTR）的淀粉样纤维形成发生在细胞外空间。因此，TTR变异体的分泌有助于淀粉样变性的发病。然而，TTR变异体内质网（ER）退出或保留以及随后降解的分子机制尚不清楚。在这里，我们证明了非分泌的TTR变体，如D18G TTR和引入单突变的淀粉样变性TTR (m -TTR)，在哺乳动物细胞中稳定地与内质网伴侣BiP相互作用。这些蛋白与分泌形式的BiP共同分泌，其中KDEL信号被去除，表明BiP部分有助于非分泌TTR变体的内质网保留。更有趣的是，当小干扰RNA下调BiP时，非分泌trs的降解效率增加。因此，BiP保护TTR变体免受立即降解。此外，我们发现非分泌型TTR变异体的稳定性在外壳复合体ii缺陷条件下不会受到干扰，这足以抑制分泌型TTR变异体（包括野生型TTR）的内质网输出。因此，er后检索机制可能不会导致非分泌TTR变异与er相关的降解。这些发现表明，与内质网驻留蛋白BiP的亲和力调节了内质网中TTR变异的命运。
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 nonsecreted 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 nonsecreted TTR variants. More interestingly, the degradation efficiency of nonsecreted TTRs was increased when BiP was down-regulated by small interfering RNA. Thus, BiP protects the TTR variants from immediate degradation. Additionally, we showed that the stability of nonsecreted TTR variants is not disturbed in the coat complex II-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 of nonsecreted TTR variants. These findings suggest that the affinity to the ER-resident protein BiP regulates the fate of TTR variants in the ER.