Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8)
Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8)
复制标题
DOI：
10.1074/jbc.m605049200
复制
发表时间：
2006-10-06
影响因子：
4.8
通讯作者：
Matsuoka, Masaaki
中科院分区：
文献类型：
--
作者：
Kanekura, Kohsuke;Nishimoto, Ikuo;Matsuoka, Masaaki
VAPB（囊泡相关膜蛋白相关蛋白B）的P56S突变导致常染色体显性运动神经元疾病。尽管有报道称P56S突变可诱导VAPB从内质网（ER）向非内质网（ER）区室的定位转移，但目前尚不清楚VAPB的生理功能以及P56S突变如何引起运动神经疾病。本研究表明，野生型VAPB （wt-VAPB）的过表达促进了未折叠蛋白反应（UPR），这是一种抑制错误折叠蛋白积累的内质网反应，并且VAPB的小干扰RNA将UPR减弱到化学诱导的内质网应激，表明VAPB在生理上参与了UPR。P56S突变通过抑制VAPB折叠导致VAPB在非er组分中的不溶性和聚集形成，从而使VAPB介导UPR的功能无效。此外，我们发现P56S-VAPB的表达通过诱导聚集形成和错定位到wt-VAPB的非er部分来抑制内源性wt-VAPB介导的UPR。因此，VAPB基因单个等位基因的P56S突变可能会使VAPB介导UPR的活性降低到正常水平的一半以下。因此，我们推测由P56S突变引起的VAPB介导UPR的功能障碍可能有助于与VAPB/ALS8相关的运动神经元变性的发展。
The P56S mutation in VAPB (vesicle-associated membrane protein-associated protein B) causes autosomal dominant motoneuronal diseases. Although it was reported that the P56S mutation induces localization shift of VAPB from endoplasmic reticulum ( ER) to non-ER compartments, it remains unclear what the physiological function of VAPB is and how the P56S mutation in VAPB causes motoneuronal diseases. Here we demonstrate that overexpression of wild type VAPB (wt-VAPB) promotes unfolded protein response (UPR), which is an ER reaction to suppress accumulation of misfolded proteins, and that small interfering RNA for VAPB attenuates UPR to chemically induced ER stresses, indicating that VAPB is physiologically involved in UPR. The P56S mutation nullifies the function of VAPB to mediate UPR by inhibiting folding of VAPB that results in insolubility and aggregate formation of VAPB in non-ER fractions. Furthermore, we have found that expression of P56S-VAPB inhibits UPR, mediated by endogenous wt-VAPB, by inducing aggregate formation and mislocalization into non-ER fractions of wt-VAPB. Consequently, the P56S mutation in a single allele of the VAPB gene may diminish the activity of VAPB to mediate UPR to less than half the normal level. We thus speculate that the malfunction of VAPB to mediate UPR, caused by the P56S mutation, may contribute to the development of motoneuronal degeneration linked to VAPB/ALS8.