Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases
Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases
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Omi/HtrA2 是自噬的正调节因子，可促进神经退行性疾病相关突变蛋白的降解
DOI：
10.1038/cdd.2010.55
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发表时间：
2010-11-01
影响因子：
12.4
通讯作者：
Wang, G.
中科院分区：
文献类型：
--
作者：
Li, B.;Hu, Q.;Wang, G.
Omi，也称为高温需要因子A2（HtrA 2），是一种丝氨酸蛋白酶，最初被鉴定为促凋亡蛋白。与Smac/Diablo一样，当在细胞凋亡刺激下释放到细胞溶质中时，它拮抗细胞凋亡蛋白的抑制剂。在mnd 2（运动神经元变性2型）小鼠中其蛋白酶活性的丧失与神经变性有关。然而，Omi调节神经退行性疾病发病机制的详细机制在很大程度上仍然未知。我们在这里报告，Omi参与了关键的细胞降解过程称为自噬。它通过消化Hax-1激活自噬，Hax-1是一种Bcl-2家族相关蛋白，在Beclin-1（酵母ATG 6的哺乳动物同源物）依赖性途径中抑制自噬。此外，Omi诱导的自噬促进神经退行性蛋白质如致病性A53 T α-突触核蛋白和截短的聚谷氨酰胺扩展的亨廷顿蛋白以及内源性自噬底物p62的降解。Omi的敲低降低了自噬的基础水平，并增加了上述靶蛋白的水平。此外，在mnd 2小鼠中发现的蛋白酶缺陷突变体S276 C Omi未能调节自噬。在mnd 2小鼠的脑中观察到增加的自噬底物和聚集结构的形成。这些结果表明Omi是一种新的自噬调节因子，并表明Omi可能在神经退行性疾病相关蛋白质的细胞质量控制中发挥重要作用。Cell Death and Differentiation（2010）17，1773-1784; doi：10.1038/cdd.2010.55; 2010年5月14日在线发表
Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T alpha-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases. Cell Death and Differentiation (2010) 17, 1773-1784; doi:10.1038/cdd.2010.55; published online 14 May 2010