FITM3充當PIP3支架來放大B細胞中的PI3K信號
作者：
小柯機器人發布時間：2020/11/6 20:23:04
美國耶魯大學Markus Mschen小組發現，IFITM3充當PIP3支架來放大B細胞中的PI3K信號。該項研究成果於2020年11月4日在線發表在《自然》雜誌上。
研究人員分析了B細胞白血病和淋巴瘤患者的臨床隊列，並確定了幹擾素誘導的跨膜蛋白3（IFITM3）是預後不良的有力預測指標。在正常的靜息B細胞中，IFITM3表達量最低，且主要位於內吞體。但是，B細胞受體（BCR）同時誘導了IFITM3的表達和該蛋白在第20位酪氨酸的磷酸化，這導致IFITM3在細胞表面積聚。在B細胞白血病中，致癌激酶使IFITM3第20位酪氨酸磷酸化，這導致該蛋白在質膜上的組成型定位。
在小鼠模型中，Ifitm3-/-初始B細胞以正常數量發育。然而，生發中心的形成和抗原特異性抗體的產生受到損害。誘導白血病和淋巴瘤發展的致癌基因不能轉化Ifitm3-/-B細胞。相反，模擬磷酸化的IFITM3（Y20E）突變體誘導致癌的PI3K信號傳導並啟動了癌前B細胞的轉化。
機制實驗表明，IFITM3充當PI3K信號的PIP3支架和核心放大器。PI3K信號的擴增依賴於IFITM3，並通過其保守的細胞片段中兩個賴氨酸殘基（第83和104位賴氨酸）作為PIP3積累的支架。在Ifitm3-/-B細胞中，脂筏中的PIP3被耗盡，這導致60多種脂筏相關的表面受體表達缺陷，並損害了BCR信號傳導和細胞粘附。
研究人員認為，在B細胞遇到抗原後發生的IFITM3磷酸化誘導了從內吞體中的抗病毒效應子功能向細胞表面PI3K放大循環的動態轉換。PI3K信號的IFITM3依賴性放大（部分作用於BCR的下遊）對於與抗原具有高親和力的B細胞快速擴增至關重要。另外，多種癌基因依賴IFITM3來組裝依賴PIP3的信號複合物，並放大PI3K信號來進行惡性轉化。
據悉，IFITM3已被鑑定為阻斷病毒感染的內吞體蛋白。
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