An Endoplasmic Reticulum (ER) Membrane Complex Composed of SPFH1 and SPFH2 Mediates the ER-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors
An Endoplasmic Reticulum (ER) Membrane Complex Composed of SPFH1 and SPFH2 Mediates the ER-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors
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DOI：
10.1074/jbc.m809801200
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发表时间：
2009-04-17
影响因子：
4.8
通讯作者：
Wojcikiewicz, Richard J. H.
中科院分区：
文献类型：
--
作者：
Pearce, Margaret M. P.;Wormer, Duncan B.;Wojcikiewicz, Richard J. H.
内质网（ER）蛋白是ER相关降解（ERAD）途径的底物，如何被识别为多聚泛素化和蛋白酶体降解在很大程度上是未解决的。肌醇1，4，5-三磷酸受体（IP（3）Rs）在ER膜中形成四聚体钙通道，其主要作用是控制ER钙储存的释放，但其水平也通过ERAD途径以激活依赖性方式调节。在这里，我们报告说，ER膜蛋白SPFH 1和它的同系物SPFH 2形成一个异聚体类似2 MDa的复合物，结合IP 3R四聚体后，立即激活，并需要为他们的处理。该复合物是环形的（直径类似于250埃），RNA干扰介导的SPFH 1和SPFH 2的消耗阻断了IP 3R多聚泛素化和降解。我们认为这种新的SPFH 1/2复合物是一种识别因子，靶向IP（3）Rs和ERAD的其他底物。
How endoplasmic reticulum (ER) proteins that are substrates for the ER-associated degradation (ERAD) pathway are recognized for polyubiquitination and proteasomal degradation is largely unresolved. Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) form tetrameric calcium channels in ER membranes, whose primary role is to control the release of ER calcium stores, but whose levels are also regulated, in an activation-dependent manner, by the ERAD pathway. Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric similar to 2 MDa complex that binds to IP3R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter similar to 250 angstrom), and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP3R polyubiquitination and degradation. We propose that this novel SPFH1/2 complex is a recognition factor that targets IP(3)Rs and perhaps other substrates for ERAD.