The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy.
The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy.
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DOI：
10.1016/j.cub.2016.12.038
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发表时间：
2017-02-06
期刊：
影响因子：
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通讯作者：
Miller CCJ
中科院分区：
文献类型：
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作者：
Gomez-Suaga P;Paillusson S;Stoica R;Noble W;Hanger DP;Miller CCJ
线粒体与调节许多生理功能的内质网（ER）形成密切的物理关联。ER区域被募集到线粒体的一种机制涉及ER蛋白VAPB与线粒体蛋白PTPIP 51的结合，其充当支架以束缚两个细胞器。在这里，我们表明VAPB-PTPIP 51系链调节自噬。我们证明，VAPB或PTPIP 51的过度表达，以收紧ER-线粒体接触损害，而小干扰RNA（siRNA）介导的VAPB或PTPIP 51的损失，以放松接触刺激，自噬体的形成。此外，我们表明人工拴系ER和线粒体的合成接头蛋白的表达也减少了自噬体的形成，并且这种人工拴系挽救了VAPB或PTPIP 51的siRNA损失对自噬的影响。因此，VAPB和PTPIP 51操纵对自噬的这些作用是其ER-线粒体束缚功能的结果。有趣的是，我们发现通过VAPB或PTPIP 51的过表达来收紧ER-线粒体接触会损害雷帕霉素和torin 1诱导的自噬，但不会损害饥饿诱导的自噬。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，我们证明了VAPB-PTPIP 51系链调节自噬的机制涉及它们在介导Ca 2+从ER储存递送到线粒体中的作用。因此，我们的研究结果揭示了一种新的调节自噬的分子机制。通过VAPB-PTPIP 51的丢失使ER-线粒体接触松动刺激自噬通过增加VAPB-PTPIP 51使ER-线粒体接触收紧抑制自噬人工ER-线粒体系链拯救VAPB-PTPIP 51丢失对自噬的影响VAPB-PTPIP 51的作用涉及它们在ER-线粒体Ca 2+递送中的作用ER和线粒体之间的紧密接触促进IP 3受体介导的Ca 2+向线粒体的递送。VAPB和PTPIP 51是介导这些接触形成的系留蛋白。Gomez-Suaga等人显示VAPB-PTPIP 51系链调节自噬，并且这涉及它们在促进ER-线粒体Ca 2+交换中的作用。
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 Ca2+ to mitochondria from ER stores. Thus, our findings reveal a new molecular mechanism for regulating autophagy. Loosening ER-mitochondria contacts by loss of VAPB-PTPIP51 stimulates autophagy Tightening ER-mitochondria contacts by increased VAPB-PTPIP51 inhibits autophagy Artificial ER-mitochondria tethers rescue VAPB-PTPIP51 loss effects on autophagy The effects of VAPB-PTPIP51 involve their role in ER-mitochondria Ca2+ delivery Tight contacts between ER and mitochondria facilitate IP3-receptor-mediated delivery of Ca2+ to mitochondria. VAPB and PTPIP51 are tethering proteins that mediate formation of these contacts. Gomez-Suaga et al. show that the VAPB-PTPIP51 tethers regulate autophagy and that this involves their role in facilitating ER-mitochondria Ca2+ exchange.