Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
Curr Biol. 2017 Feb 6;27(3):371-385. doi: 10.1016/j.cub.2016.12.038. Epub 2017 Jan 26.
Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions of ER are recruited to mitochondria involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51, which act as scaffolds to tether the two organelles. Here, we show that the VAPB-PTPIP51 tethers regulate autophagy. We demonstrate that overexpression of VAPB or PTPIP51 to tighten ER-mitochondria contacts impairs, whereas small interfering RNA (siRNA)-mediated loss of VAPB or PTPIP51 to loosen contacts stimulates, autophagosome formation. Moreover, we show that expression of a synthetic linker protein that artificially tethers ER and mitochondria also reduces autophagosome formation, and that this artificial tether rescues the effects of siRNA loss of VAPB or PTPIP51 on autophagy. Thus, these effects of VAPB and PTPIP51 manipulation on autophagy are a consequence of their ER-mitochondria tethering function. Interestingly, we discovered that tightening of ER-mitochondria contacts by overexpression of VAPB or PTPIP51 impairs rapamycin- and torin 1-induced, but not starvation-induced, autophagy. This suggests that the regulation of autophagy by ER-mitochondria signaling is at least partly dependent upon the nature of the autophagic stimulus. Finally, we demonstrate that the mechanism by which the VAPB-PTPIP51 tethers regulate autophagy involves their role in mediating delivery of Ca to mitochondria from ER stores. Thus, our findings reveal a new molecular mechanism for regulating autophagy.
线粒体与内质网（ER）形成紧密的物理关联，调节许多生理功能。ER 区域被招募到线粒体的一种机制涉及 ER 蛋白 VAPB 与线粒体蛋白 PTPIP51 的结合，它们作为支架将两个细胞器连接在一起。在这里，我们表明 VAPB-PTPIP51 连接体调节自噬。我们证明，过度表达 VAPB 或 PTPIP51 以收紧 ER-线粒体接触会损害自噬体的形成，而通过小干扰 RNA（siRNA）介导的 VAPB 或 PTPIP51 的缺失以放松接触则会刺激自噬体的形成。此外，我们表明表达一种人工连接 ER 和线粒体的连接蛋白也会减少自噬体的形成，并且这种人工连接可以挽救 VAPB 或 PTPIP51 的 siRNA 缺失对自噬的影响。因此，VAPB 和 PTPIP51 对自噬的这种影响是其 ER-线粒体连接功能的结果。有趣的是，我们发现通过过度表达 VAPB 或 PTPIP51 收紧 ER-线粒体接触会损害雷帕霉素和 torin 1 诱导的，但不是饥饿诱导的自噬。这表明 ER-线粒体信号对自噬的调节至少部分依赖于自噬刺激的性质。最后，我们证明 VAPB-PTPIP51 连接体调节自噬的机制涉及它们在介导 Ca 从 ER 库向线粒体运输中的作用。因此，我们的发现揭示了调节自噬的新分子机制。
