Here, we report that the RTN3L-SEC24C endoplasmic reticulum autophagy (ER-phagy) receptor complex, the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L, and the FIP200 autophagy initiating protein, target mutant proinsulin (Akita) condensates for lysosomal delivery at ER tubule junctions. When delivery was blocked, Akita condensates accumulated in the ER. In exploring the role of tubulation in these events, we unexpectedly found that loss of the Parkinson's disease protein, PINK1, reduced peripheral tubule junctions and blocked ER-phagy. Overexpression of the PINK1 kinase substrate, DRP1, increased junctions, reduced Akita condensate accumulation, and restored lysosomal delivery in PINK1-depleted cells. DRP1 is a dual-functioning protein that promotes ER tubulation and severs mitochondria at ER-mitochondria contact sites. DRP1-dependent ER tubulating activity was sufficient for suppression. Supporting these findings, we observed PINK1 associating with ER tubules. Our findings show that PINK1 shapes the ER to target misfolded proinsulin for RTN3L-SEC24C-mediated macro-ER-phagy at defined ER sites called peripheral junctions. These observations may have important implications for understanding Parkinson's disease.

中文翻译：

---

PINK1 通过调节外周肾小管连接来控制 RTN3L 介导的 ER 自噬。


在这里，我们报道了 RTN3L-SEC24C 内质网自噬 （ER-phagy） 受体复合物、泛素化 RTN3L 的 CUL3KLHL12 E3 连接酶和 FIP200 自噬起始蛋白，靶向突变体胰岛素原 （Akita） 凝聚物，用于在 ER 小管连接处进行溶酶体递送。当输送受阻时，秋田冷凝物在 ER 中积聚。在探索输管在这些事件中的作用时，我们出乎意料地发现帕金森病蛋白 PINK1 的缺失减少了外周肾小管连接并阻断了 ER 吞噬。PINK1 激酶底物 DRP1 的过表达增加了连接，减少了秋田浓缩物的积累，并恢复了 PINK1 耗尽细胞中的溶酶体递送。DRP1 是一种双功能蛋白，可促进 ER 管形成并切断 ER 线粒体接触位点的线粒体。DRP1 依赖性 ER 管活动足以抑制。支持这些发现，我们观察到 PINK1 与 ER 小管相关。我们的研究结果表明，PINK1 塑造 ER 以靶向错误折叠的胰岛素原，用于 RTN3L-SEC24C 介导的宏 ER 自噬，位于称为外周连接的特定 ER 位点。这些观察结果可能对理解帕金森病具有重要意义。