ER-stress-inducible Herp, facilitates the degradation of immature nicastrin
ER-stress-inducible Herp, facilitates the degradation of immature nicastrin
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DOI：
10.1016/j.bbagen.2011.04.017
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发表时间：
2011-08-01
影响因子：
3
通讯作者：
Komano, Hiroto
中科院分区：
文献类型：
--
作者：
Marutani, Toshihiro;Maeda, Tomoji;Komano, Hiroto
背景：Herp是一种内质网应激诱导的膜蛋白，具有泛素样结构域（ULD）。然而，其生物学功能尚未完全了解。在这里，我们研究的作用，Herp在γ-secretasecomponents.Methods的降解ULD缺乏Herp（Δ Ub-Herp）的表达对γ-secretasecomponents.Results的降解的影响进行了分析：Δ Ub-Herp的细胞表达被发现抑制过表达的未成熟nicastrin和全长早老素的降解。进一步分析了Herp介导的nicastrin降解的机制。我们发现，未成熟的nicastrin积累在ER的Δ Ub-Herp过表达细胞或Herp缺陷细胞比在ER的野生型细胞。此外，Δ Ub-Herp表达抑制nicastrin泛素化，表明Herp的ULD可能参与nicastrin泛素化。免疫共沉淀研究表明，Herp以及Delta Ub-Herp可能与nicastrin相互作用，介导nicastrin与p97的相互作用，p97的功能是将错误折叠的蛋白质从ER重转位到cytosol.Conclusions：因此，Herp可能通过促进p97依赖的nicastrin重转位和泛素化参与未成熟nicastrin的降解。一般意义：我们认为Herp可以在消除多聚体复合物中多余的未组装成分中发挥作用。(C)2011爱思唯尔有限公司版权所有。
Background: Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein harboring an ubiquitin-like domain (ULD). However, its biological functions are not fully understood. Here, we examined the role of Herp in the degradation of gamma-secretase components.Methods: Effects of ULD-lacking Herp (Delta Ub-Herp) expression on the degradation of gamma-secretase components were analyzed.Results: The cellular expression of Delta Ub-Herp was found to inhibit the degradation of overexpressed immature nicastrin and full-length presenilin. The mechanisms underlying Herp-mediated nicastrin degradation was further analyzed. We found that immature nicastrin accumulates in the ER of Delta Ub-Herp overexpressing cells or Herp-deficient cells more than that in the ER of wild-type cells. Further, Delta Ub-Herp expression inhibited nicastrin ubiquitination, suggesting that the ULD of Herp is likely involved in nicastrin ubiquitination. Co-immunoprecipitation study showed that Herp as well as Delta Ub-Herp potentially interacts with nicastrin, mediating nicastrin interaction with p97, which functions in retranslocation of misfolded proteins from the ER to the cytosol.Conclusions: Thus, Herp is likely involved in degradation of immature nicastrin by facilitating p97-dependent nicastrin retranslocation and ubiquitination. General significance: We suggest that Herp could play a role in the elimination of the excess unassembled components of a multimeric complex. (C) 2011 Elsevier B.V. All rights reserved.