Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II)
Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II)
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DOI：
10.1093/hmg/ddm002
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发表时间：
2007-03-15
影响因子：
3.5
通讯作者：
Momoi, Takashi
中科院分区：
文献类型：
--
作者：
Fujita, Eriko;Kouroku, Yoriko;Momoi, Takashi
Dysferlin是一种II型跨膜蛋白，是肢带型肌营养不良症2B型和三好肌病（LGMD 2B/MM）的致病基因，其中经常观察到dysferlin标记的特异性丢失。最近，一种新的突变体（L1341 P）dysferlin已被证明在患者的肌肉中聚集。关于dysferlin降解与LGMD 2B/MM发病机制之间的关系知之甚少。在这里，我们研究了正常和突变型（L1341 P）dysferlin的降解。野生型dysferlin主要定位于内质网/高尔基体，与逆转录转位子、Sec 61 α和VCP（p97）相关，并被由泛素/蛋白酶体组成的内质网（ER）相关降解系统（ERAD）降解。相比之下，突变dysferlin自发聚集在ER中，并诱导真核翻译起始因子2 α（eIF 2 α）磷酸化和LC 3转化，这是自噬体形成的关键步骤，最终导致ER应激细胞死亡。与蛋白酶体抑制剂E64 d/胃蛋白酶抑制剂A不同，溶酶体蛋白酶抑制剂不刺激wt-dysferlin的积累，但刺激突变型dysferlin在ER中的聚集。此外，Atg 5的缺陷和eIF 2 α的去磷酸化，LC 3转换的关键分子，也刺激了突变dysferlin聚集在ER。诱导eIF 2 α磷酸化介导的LC 3转化的雷帕霉素抑制ER中的突变dysferlin聚集。因此，突变dysferlin聚集在ER刺激的自噬体形成中，通过激活ER应激-eIF 2 α磷酸化途径吞噬它们。我们提出了两个ERAD模型dysferlin降解，泛素/蛋白酶体ERAD（I）和自噬/溶酶体ERAD（II）。ER上的突变dysferlin聚集体被自噬/溶酶体ERAD（II）降解，作为ERAD（I）的替代，当逆转录转运子/ERAD（I）系统被这些突变聚集体损害时。
Dysferlin is a type-II transmembrane protein and the causative gene of limb girdle muscular dystrophy type 2B and Miyoshi myopathy (LGMD2B/MM), in which specific loss of dysferlin labeling has been frequently observed. Recently, a novel mutant (L1341P) dysferlin has been shown to aggregate in the muscle of the patient. Little is known about the relationship between degradation of dysferlin and pathogenesis of LGMD2B/MM. Here, we examined the degradation of normal and mutant (L1341P) dysferlin. Wild-type (wt) dysferlin mainly localized to the ER/Golgi, associated with retrotranslocon, Sec61 alpha, and VCP(p97), and was degraded by endoplasmic reticulum (ER)-associated degradation system (ERAD) composed of ubiquitin/proteasome. In contrast, mutant dysferlin spontaneously aggregated in the ER and induced eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation and LC3 conversion, a key step for autophagosome formation, and finally, ER stress cell death. Unlike proteasome inhibitor, E64d/pepstatin A, inhibitors of lysosomal proteases did not stimulate the accumulation of the wt-dysferlin, but stimulated aggregation of mutant dysferlin in the ER. Furthermore, deficiency of Atg5 and dephosphorylation of eIF2 alpha, key molecules for LC3 conversion, also stimulated the mutant dysferlin aggregation in the ER. Rapamycin, which induces eIF2 alpha phosphorylation-mediated LC3 conversion, inhibited mutant dysferlin aggregation in the ER. Thus, mutant dysferlin aggregates in the ER-stimulated autophagosome formation to engulf them via activation of ER stress-eIF2 alpha phosphorylation pathway. We propose two ERAD models for dysferlin degradation, ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Mutant dysferlin aggregates on the ER are degraded by the autophagy/lysosome ERAD(II), as an alternative to ERAD(I), when retrotranslocon/ERAD(I) system is impaired by these mutant aggregates.