Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 3043, Ann Arbor, MI, 48109, USA.
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA.
Nat Commun. 2021 Oct 13;12(1):5991. doi: 10.1038/s41467-021-26225-8.
The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-deficiency. Chemical perturbation of PGRMC1 partially restores WT insulin storage by preventing ER-phagic degradation of WT and mutant proinsulin. Thus, PGRMC1 acts as a size-selective cargo receptor during RTN3-dependent ER-phagy, and is a potential therapeutic target for diabetes.
网质蛋白 3（RTN3）驱动的靶向复合物促进内质网（ER）中错误折叠的激素原从 ER 中清除，然后通过 ER 噬作用被溶酶体破坏。由于 RTN3 位于 ER 双层的胞质小叶中，因此 ER 膜的腔侧选择错误折叠的激素原作为 ER 噬作用货物的机制仍不清楚。在这里，我们鉴定出内质网跨膜蛋白 PGRMC1 是 RTN3 的结合伴侣。通过其腔域，PGRMC1 捕获错误折叠的激素原，将其靶向 RTN3 依赖性 ER 噬作用。PGRMC1 选择的货物小于其他报道的 ER 噬作用底物的较大尺寸。PGRMC1 的货物包括突变的前胰岛素，这些突变的前胰岛素通过在 ER 内的显性负相互作用阻断野生型前胰岛素的分泌，导致胰岛素缺乏。化学扰动 PGRMC1 可通过防止 WT 和突变前胰岛素的 ER 噬性降解，部分恢复 WT 胰岛素的储存，从而恢复 WT 胰岛素的储存。因此，PGRMC1 在 RTN3 依赖性 ER 噬作用过程中作为大小选择性货物受体发挥作用，是治疗糖尿病的潜在治疗靶点。
