Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11559-64. doi: 10.1073/pnas.1307032110. Epub 2013 Jun 24.
Defects in normal autophagic pathways are implicated in numerous human diseases--such as neurodegenerative diseases, cancer, and cardiomyopathy--highlighting the importance of autophagy and its proper regulation. Herein we show that Vibrio parahaemolyticus uses the type III effector VopQ (Vibrio outer protein Q) to alter autophagic flux by manipulating the partitioning of small molecules and ions in the lysosome. This effector binds to the conserved Vo domain of the vacuolar-type H(+)-ATPase and causes deacidification of the lysosomes within minutes of entering the host cell. VopQ forms a gated channel ∼18 Å in diameter that facilitates outward flux of ions across lipid bilayers. The electrostatic interactions of this type 3 secretion system effector with target membranes dictate its preference for host vacuolar-type H(+)-ATPase-containing membranes, indicating that its pore-forming activity is specific and not promiscuous. As seen with other effectors, VopQ is exploiting a eukaryotic mechanism, in this case manipulating lysosomal homeostasis and autophagic flux through transmembrane permeation.
正常自噬途径的缺陷与许多人类疾病有关，如神经退行性疾病、癌症和心肌病等，这凸显了自噬及其适当调节的重要性。本文中我们表明，副溶血弧菌利用 III 型效应蛋白 VopQ（弧菌外蛋白 Q）通过操纵溶酶体中小分子和离子的分配来改变自噬流。该效应蛋白与液泡型 H(+)-ATP 酶的保守 Vo 结构域结合，并在进入宿主细胞后的几分钟内导致溶酶体去酸化。VopQ 形成一个直径约为 18Å 的门控通道，促进离子穿过脂质双层的外向流动。这种 III 型分泌系统效应蛋白与靶膜的静电相互作用决定了其对宿主液泡型 H(+)-ATP 酶含有的膜的偏好性，表明其孔形成活性是特异性的，而不是随意的。与其他效应蛋白一样，VopQ 利用了一种真核机制，即通过跨膜渗透来操纵溶酶体稳态和自噬流。
