a Department of Basic and Clinical Neuroscience , Institute of Psychiatry, Psychology and Neuroscience, Kings College London , London , UK.
Autophagy. 2017 Jul 3;13(7):1250-1251. doi: 10.1080/15548627.2017.1317913. Epub 2017 May 26.
The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves "tethering proteins" that function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca from ER stores to mitochondria.
内质网（ER）和线粒体形成紧密的功能联系，调节几个关键的细胞过程。这些联系的形成涉及“ tethering proteins ”，它们的功能是将 ER 的区域募集到线粒体。完整的 ER 蛋白 VAPB（VAMP 相关蛋白 B 和 C）与线粒体的外膜蛋白 RMDN3/PTPIP51（微管动态调节因子 3）结合，形成这样的一组系链。最近，我们发现 VAPB-RMDN3 系链调节巨自噬/自噬。用小干扰 RNA（siRNA）敲低 VAPB 或 RMDN3 以松开 ER-线粒体接触会刺激自噬体的形成，而 VAPB 或 RMDN3 的过表达以收紧接触会抑制其形成。通过表达合成连接蛋白来人工系链 ER 和线粒体也会减少自噬，并且这种人工系链可以挽救 VAPB 或 RMDN3 靶向 siRNA 损失对自噬体形成的影响。最后，我们的研究表明，ER-线粒体接触对自噬的调节作用涉及它们在介导 ITPR（三磷酸肌醇受体）将 Ca 从 ER 库传递到线粒体中的作用。
