Krick Stefanie, Shi Shaolin, Ju Wenjun, Faul Christian, Tsai Su-yi, Mundel Peter, Böttinger Erwin P
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14106-11. doi: 10.1073/pnas.0801146105. Epub 2008 Sep 4.
Cellular localization determines whether the serine protease HtrA2 exerts pro- or antiapoptotic functions. In contrast to the well-characterized proapoptotic function of cytosolic HtrA2, mechanisms underlying the mitochondrial protective role are poorly understood. Mpv17l is a transmembrane protein previously implicated in peroxisomal reactive oxygen species metabolism and a close homolog of the inner mitochondrial membrane protein Mpv17. Here we demonstrate a previously undescribed direct interaction between Mpv17l and HtrA2 in mitochondria. The interaction is mediated by a PDZ domain and induces protease activation of HtrA2. HtrA2 inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular inducers of mitochondrial stress. The physiological role of Mpv17l is underscored by the finding that oxidative stress-induced downregulation of Mpv17l is a consistent feature in renal injury models. Our findings identify Mpv17l as a unique interacting protein and regulator of HtrA2 protease mediating antioxidant and antiapoptotic function in mitochondria.
细胞定位决定了丝氨酸蛋白酶HtrA2发挥促凋亡还是抗凋亡功能。与胞质HtrA2已明确的促凋亡功能不同,线粒体保护作用的潜在机制尚不清楚。Mpv17l是一种跨膜蛋白,先前被认为与过氧化物酶体活性氧代谢有关,是线粒体内膜蛋白Mpv17的紧密同源物。在这里,我们证明了Mpv17l与线粒体中的HtrA2之间存在一种先前未描述的直接相互作用。这种相互作用由一个PDZ结构域介导,并诱导HtrA2的蛋白酶激活。HtrA2抑制线粒体超氧化物的产生,稳定线粒体膜电位,并在基线状态以及应对线粒体应激的细胞外诱导剂时防止细胞凋亡。肾损伤模型中氧化应激诱导的Mpv17l下调是一个一致的特征,这一发现突出了Mpv17l的生理作用。我们的研究结果确定Mpv17l是一种独特的相互作用蛋白,也是HtrA2蛋白酶的调节剂,介导线粒体中的抗氧化和抗凋亡功能。