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NINJ1在溶解性细胞死亡期间介导质膜破裂
2021-01-21 12:42

美国基因泰克公司Vishva M. Dixit、Nobuhiko Kayagaki等研究人员合作发现,NINJ1在溶解性细胞死亡期间介导质膜破裂。该项研究成果于2021年1月20日在线发表在《自然》杂志上。

研究人员表示,质膜破裂(PMR)是裂解细胞死亡的最后一次灾难性事件。PMR释放细胞内分子,称为损伤相关分子模式(DAMP),可传播炎症反应。但是,PMR的基本机制尚不清楚。

研究人员表明,疾病特征性神经损伤诱导蛋白1(NINJ1,一种具有两个跨膜区域的细胞表面蛋白)在PMR的诱导中起着至关重要的作用。随机诱变小鼠的前向筛选将NINJ1与PMR联系起来。Ninj1–/–巨噬细胞对细胞焦亡、坏死性和凋亡性细胞死亡的多种诱导物表现出PMR受损,并且未能释放大量细胞内蛋白,包括HMGB1(一种已知的DAMP)和乳酸脱氢酶(LDH,标准PMR的度量)。Ninj1–/–巨噬细胞发生死亡,但具有独特且持续的气球状形态,这是由于气泡状突出的崩解不良。Ninj1–/–小鼠比野生型小鼠更易受啮齿类柠檬酸杆菌的侵害,这表明PMR在抗菌宿主防御中起着重要作用。

从机理上讲,NINJ1利用进化上保守的胞外域进行寡聚化和随后的PMR。NINJ1作为PMR的介导分子的发现推翻了长期存在的教条,即与细胞死亡相关的PMR是被动事件。

附:英文原文

Title: NINJ1 mediates plasma membrane rupture during lytic cell death

Author: Nobuhiko Kayagaki, Opher S. Kornfeld, Bettina L. Lee, Irma B. Stowe, Karen ORourke, Qingling Li, Wendy Sandoval, Donghong Yan, Jing Kang, Min Xu, Juan Zhang, Wyne P. Lee, Brent S. McKenzie, Gzde Ulas, Jian Payandeh, Merone Roose-Girma, Zora Modrusan, Rohit Reja, Meredith Sagolla, Joshua D. Webster, Vicky Cho, T. Daniel Andrews, Lucy X. Morris, Lisa A. Miosge, Christopher C. Goodnow, Edward M. Bertram, Vishva M. Dixit

Issue&Volume: 2021-01-20

Abstract: Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules termed damage-associated molecular patterns (DAMPs) that propagate the inflammatory response1–3. The underlying mechanism for PMR, however, is unknown. Here we show that the ill-characterized nerve injury-induced protein 1 (NINJ1)4–8 — a cell surface protein with two transmembrane regions — plays an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1–/– macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and failed to release numerous intracellular proteins including High Mobility Group Box 1 (HMGB1, a known DAMP) and Lactate Dehydrogenase (LDH, a standard measure of PMR). Ninj1–/– macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1–/– mice were more susceptible than wild-type mice to Citrobacter rodentium, suggesting a role for PMR in anti-bacterial host defense. Mechanistically, NINJ1 utilized an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held dogma that cell death-related PMR is a passive event.

DOI: 10.1038/s41586-021-03218-7

Source: https://www.nature.com/articles/s41586-021-03218-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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