Complement Membrane Attack Complexes Disrupt Proteostasis to Function as Intracellular Alarmins.

Research square Pub Date : 2024-06-19 DOI:10.21203/rs.3.rs-4504419/v1

Dan Jane-Wit, Guiyu Song, Liying He, Quan Jiang, Mahsa Barkestani, Shaoxun Wang, Qianxun Wang, Pengwei Ren, Matthew Fan, Justin Johnson, Clancy Mullan

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Abstract

Internalized pools of membrane attack complexes (MACs) promote NF-kB and dysregulated tissue inflammation. Here, we show that C9, a MAC-associated protein, promotes loss of proteostasis to become intrinsically immunogenic. Surface-bound C9 is internalized into Rab5 + endosomes whose intraluminal acidification promotes C9 aggregates. A region within the MACPF/CDC domain of C9 stimulates aggrephagy to induce NF-kB, inflammatory genes, and EC activation. This process requires ZFYVE21, a Rab5 effector, which links LC3A/B on aggresome membranes to RNF34-P62 complexes to mediate C9 aggrephagy. C9 aggregates form in human tissues, C9-associated signaling responses occur in three mouse models, and ZFYVE21 stabilizes RNF34 to promote C9 aggrephagy in vivo. Gene-deficient mice lacking ZFYVE21 in ECs showed reduced MAC-induced tissue injury in a skin model of chronic rejection. While classically defined as cytotoxic effectors, MACs may impair proteostasis, forming aggregates that behave as intracellular alarmins.

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补体膜攻击复合物破坏蛋白稳态，发挥细胞内 Alarmins 的功能。

内化的膜攻击复合物（MAC）池会促进 NF-kB 和失调的组织炎症。在这里，我们发现 C9（一种 MAC 相关蛋白）会促进蛋白稳态的丧失，从而成为内在免疫原。表面结合的 C9 内化成 Rab5 + 内体，其腔内酸化促进了 C9 的聚集。C9 的 MACPF/CDC 结构域内的一个区域会刺激凝集，从而诱导 NF-kB、炎症基因和 EC 活化。这一过程需要 Rab5 效应器 ZFYVE21，它将凝集体膜上的 LC3A/B 与 RNF34-P62 复合物连接起来，从而介导 C9 的凝集。C9聚集体在人体组织中形成，C9相关信号反应在三种小鼠模型中出现，ZFYVE21能稳定RNF34，促进体内C9的凝集。在慢性排斥的皮肤模型中，缺乏 ZFYVE21 的基因缺陷小鼠显示出 MAC 诱导的组织损伤减少。虽然MAC被经典地定义为细胞毒性效应物，但它可能会损害蛋白稳态，形成可作为细胞内警戒素的聚集体。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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