小柯机器人

FITM3充当PIP3支架来放大B细胞中的PI3K信号
2020-11-06 20:23

美国耶鲁大学Markus Mschen小组发现,IFITM3充当PIP3支架来放大B细胞中的PI3K信号。该项研究成果于2020年11月4日在线发表在《自然》杂志上。

研究人员分析了B细胞白血病和淋巴瘤患者的临床队列,并确定了干扰素诱导的跨膜蛋白3(IFITM3)是预后不良的有力预测指标。在正常的静息B细胞中,IFITM3表达量最低,且主要位于内吞体。但是,B细胞受体(BCR)同时诱导了IFITM3的表达和该蛋白在第20位酪氨酸的磷酸化,这导致IFITM3在细胞表面积聚。在B细胞白血病中,致癌激酶使IFITM3第20位酪氨酸磷酸化,这导致该蛋白在质膜上的组成型定位。
 
在小鼠模型中,Ifitm3-/-初始B细胞以正常数量发育。然而,生发中心的形成和抗原特异性抗体的产生受到损害。诱导白血病和淋巴瘤发展的致癌基因不能转化Ifitm3-/-B细胞。相反,模拟磷酸化的IFITM3(Y20E)突变体诱导致癌的PI3K信号传导并启动了癌前B细胞的转化。
 
机制实验表明,IFITM3充当PI3K信号的PIP3支架和核心放大器。PI3K信号的扩增依赖于IFITM3,并通过其保守的细胞片段中两个赖氨酸残基(第83和104位赖氨酸)作为PIP3积累的支架。在Ifitm3-/-B细胞中,脂筏中的PIP3被耗尽,这导致60多种脂筏相关的表面受体表达缺陷,并损害了BCR信号传导和细胞粘附。
 
研究人员认为,在B细胞遇到抗原后发生的IFITM3磷酸化诱导了从内吞体中的抗病毒效应子功能向细胞表面PI3K放大循环的动态转换。PI3K信号的IFITM3依赖性放大(部分作用于BCR的下游)对于与抗原具有高亲和力的B细胞快速扩增至关重要。另外,多种癌基因依赖IFITM3来组装依赖PIP3的信号复合物,并放大PI3K信号来进行恶性转化。
 
据悉,IFITM3已被鉴定为阻断病毒感染的内吞体蛋白。
 
附:英文原文

Title: IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells

Author: Jaewoong Lee, Mark E. Robinson, Ning Ma, Dewan Artadji, Mohamed A. Ahmed, Gang Xiao, Teresa Sadras, Gauri Deb, Janet Winchester, Kadriye Nehir Cosgun, Huimin Geng, Lai N. Chan, Kohei Kume, Teemu P. Miettinen, Ye Zhang, Matthew A. Nix, Lars Klemm, Chun Wei Chen, Jianjun Chen, Vishal Khairnar, Arun P. Wiita, Andrei Thomas-Tikhonenko, Michael Farzan, Jae U. Jung, David M. Weinstock, Scott R. Manalis, Michael S. Diamond, Nagarajan Vaidehi, Markus Mschen

Issue&Volume: 2020-11-04

Abstract: Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1,2,3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3/ naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3/ B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3/ B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.

DOI: 10.1038/s41586-020-2884-6

Source: https://www.nature.com/articles/s41586-020-2884-6

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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