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溶酶体与 WIPI1 环和 ER 连接的吞噬体的对接发生在 DNAJB12 和 GABARAP 依赖性的错误折叠 P23H-视蛋白的选择性自噬过程中。

Lysosome docking to WIPI1 rings and ER-connected phagophores occurs during DNAJB12- and GABARAP-dependent selective autophagy of misfolded P23H-rhodopsin.

机构信息

Department of Cell Biology and Physiology, School of Medicine, and.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

出版信息

Mol Biol Cell. 2022 Aug 1;33(9):ar84. doi: 10.1091/mbc.E21-10-0505. Epub 2022 Jun 15.

Abstract

We report on how the endoplasmic reticulum (ER)-associated-autophagy pathway (ERAA) delivers P23H-rhodopsin (P23H-R) to the lysosome. P23H-R accumulates in an ERAD-resistant conformation that is stabilized in a detergent-soluble state by DNAJB12 and Hsp70. P23H-R, DNAJB12, and FIP200 colocalize in discrete foci that punctuate the rim of omegasome rings coated by WIPI1. Loss of DNAJB12 function prevents the association of P23H-R containing ER tubules with omegasomes. P23H-R tubules thread through the wall of WIPI1 rings into their central cavity. Transfer of P23H-R from ER-connected phagophores to lysosomes requires GABARAP and is associated with the transient docking of lysosomes to WIPI1 rings. After departure from WIPI1 rings, new patches of P23H-R are seen in the membranes of lysosomes. The absence of GABARAP prevents transfer of P23H-R from phagophores to lysosomes without interfering with docking. These data identify lysosome docking to omegasomes as an important step in the DNAJB12- and GABARAP-dependent autophagic disposal of dominantly toxic P23H-R.

摘要

我们报告内质网(ER)相关自噬途径(ERAA)如何将 P23H-视蛋白(P23H-R)递送至溶酶体。P23H-R 以 ERAD 抗性构象积累,该构象通过 DNAJB12 和 Hsp70 稳定在去污剂可溶状态中。P23H-R、DNAJB12 和 FIP200 共定位于离散焦点,这些焦点突出了由 WIPI1 覆盖的 omegasome 环的边缘。DNAJB12 功能的丧失阻止了含有 P23H-R 的 ER 小管与 omegasome 的关联。P23H-R 小管穿过 WIPI1 环的壁进入其中心腔。从与 ER 相连的吞噬体向溶酶体转移 P23H-R 需要 GABARAP,并且与溶酶体与 WIPI1 环的短暂对接相关。离开 WIPI1 环后,新的 P23H-R 斑块出现在溶酶体的膜中。缺乏 GABARAP 会阻止 P23H-R 从吞噬体转移到溶酶体,而不会干扰对接。这些数据表明,溶酶体与 omegasome 的对接是 DNAJB12 和 GABARAP 依赖的自噬性处理显性毒性 P23H-R 的重要步骤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5da/9582645/3f633ea9ea77/mbc-33-ar84-g001.jpg

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