HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function
HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function
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DOI：
10.1096/fj.11-196063
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发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
--
作者：
Hayashi, Hiroki;Nakagami, Hironori;Kaneda, Yasufumi
γ-分泌酶复合物（含有早老素、nicastrin、前咽缺陷-1和早老素增强子-2）切割I型跨膜蛋白，包括Notch和淀粉样前体蛋白。γ-分泌酶活性失调与阿尔茨海默病、中风、动脉粥样硬化和癌症的发病机制有关。γ-分泌酶活性的严格调节是正常生理所必需的。在这里，我们从γ-分泌酶抑制基因的功能筛选中分离出了HIGH 1（缺氧诱导基因1，结构域成员1A）。HIGH 1在脑组织中高表达。有趣的是，在SK-N-SH神经母细胞瘤细胞中，HIGH 1定位于线粒体，并直接与线粒体膜上的γ-分泌酶组分结合。HIGH 1的过度表达减弱了缺氧诱导的线粒体膜γ-分泌酶激活和细胞内淀粉样β蛋白的积累。这种积累伴随着缺氧诱导的线粒体功能障碍。HIG 1的后半结构域是结合γ-分泌酶复合物和抑制γ-分泌酶活性所必需的。此外，HIGH 1的耗竭增加了γ-分泌酶的激活，并增强了缺氧诱导的线粒体功能障碍。总之，HIG 1是线粒体γ-分泌酶复合物的新型调节剂，可能在维持正常线粒体功能中发挥作用。林，H.，Nakagami，H.，Takeichi，M.，Shimamura，M.，Koibuchi，N.，Oiki，E.，佐藤，N.，Koriyama，H.，莫里，M.，Gerardo Araujo，R.，Maeda，A.，森下河塔迈，K.，Kaneda，Y. HIG 1是一种新的线粒体γ-分泌酶调节因子，维持正常的线粒体功能。FASEB J.26，2306-2317（2012）。www.fasebj.org
The gamma-secretase complex (which contains presenilins, nicastrin, anterior pharynx defective-1, and presenilin enhancer-2) cleaves type I transmembrane proteins, including Notch and amyloid precursor protein. Dysregulated gamma-secretase activity has been implicated in the pathogenesis of Alzheimer's disease, stroke, atherosclerosis, and cancer. Tight regulation of gamma-secretase activity is required for normal physiology. Here, we isolated HIG1 (hypoxia inducible gene 1, domain member 1A) from a functional screen of gamma-secretase inhibitory genes. HIG1 was highly expressed in the brain. Interestingly, HIG1 was localized to the mitochondria and was directly bound to gamma-secretase components on the mitochondrial membrane in SK-N-SH neuroblastoma cells. Overexpresssion of HIG1 attenuated hypoxia-induced gamma-secretase activation on the mitochondrial membrane and the accumulation of intracellular amyloid beta. This accumulation was accompanied by hypoxia-induced mitochondrial dysfunction. The latter half domain of HIG1 was required for binding to the gamma-secretase complex and suppression of gamma-secretase activity. Moreover, depletion of HIG1 increased gamma-secretase activation and enhanced hypoxia-induced mitochondrial dysfunction. In summary, HIG1 is a novel modulator of the mitochondrial gamma-secretase complex, and may play a role in the maintenance of normal mitochondrial function.-Hayashi, H., Nakagami, H., Takeichi, M., Shimamura, M., Koibuchi, N., Oiki, E., Sato, N., Koriyama, H., Mori, M., Gerardo Araujo, R., Maeda, A., Morishita, R., Tamai, K., Kaneda, Y. HIG1, a novel regulator of mitochondrial gamma-secretase, maintains normal mitochondrial function. FASEB J. 26, 2306-2317 (2012). www.fasebj.org