人类生发中心相关淋巴瘤(HGAL)衔接蛋白在细胞信号传导和淋巴成像中的作用

Xiaoyu Jiang, I. Lossos
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引用次数: 0

摘要

人生发中心(GC)相关淋巴瘤(HGAL)是一种多结构域衔接蛋白,表达于GC B淋巴细胞、T滤泡辅助细胞(Tfh)和源自这些细胞的淋巴瘤。HGAL表达是弥漫性大b细胞淋巴瘤(DLBCL)和经典霍奇金淋巴瘤(HL)患者生存时间延长的独立预测因子。HGAL通过与下游效应物[如脾酪氨酸激酶(Syk)]或其他信号调节物[如生长因子受体结合蛋白2 (Grb2)]结合,调节B细胞受体(BCR)信号传导和免疫突触的形成。HGAL通过至少两种分子机制调节BCR信号传导和细胞运动过程中重塑B细胞形态的细胞骨架:增强Ras同源基因家族成员A (RhoA)信号传导和抑制肌球蛋白-肌动蛋白易位。这些对细胞骨架的影响减少了动物模型中的淋巴瘤传播,并有助于减少患者的淋巴瘤传播。后者可能有助于HGAL蛋白表达与DLBCL和HL肿瘤患者更长的生存期相关。在B细胞中同时调节多种不同功能的能力表明HGAL蛋白水平受到严格调节。结果表明,HGAL可以在转录水平上受PR/SET结构域1 (PRDM1)/B淋巴细胞诱导成熟蛋白1 (BLIMP1)和白介素-4 (IL-4)的调控,在转录后水平上受microRNA-155 (miR-155)的调控,在翻译后水平上受F-box蛋白10 (FBXO10)的调控。HGAL在生理水平上的组成性强制表达导致小鼠淋巴样增生和大细胞淋巴瘤。未来的研究需要重点确定HGAL相互作用组,剖析其相互作用网络,了解生理条件下活细胞中HGAL的时空信号。此外,最近证明HGAL在Tfh细胞中的表达需要确定其在这些细胞中的功能。这些研究将有助于对这些细胞亚群的生物学以及免疫失调如何导致淋巴瘤发生提供新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of an adaptor protein human germinal center-associated lymphoma (HGAL) in cell signaling and lymphomagenesis
Human germinal center (GC)-associated lymphoma (HGAL) is a multi-domain adaptor protein expressed in GC B lymphocytes, T follicular helper (Tfh) cells and lymphomas derived from these cells. HGAL expression is an independent predictor of longer survival of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (HL) patients. HGAL regulates B cell receptor (BCR) signaling and immunological synapse formation by binding to either the downstream effectors [e.g., spleen tyrosine kinase (Syk)] or other signaling regulators [e.g., growth factor receptor-bound protein 2 (Grb2)]. HGAL regulates the cytoskeleton that reshapes B cell morphology during BCR signaling and cell motility by at least two molecular mechanisms: enhanced Ras homolog gene family member A (RhoA) signaling and inhibition of myosin-actin translocation. These effects on the cytoskeleton decrease lymphoma dissemination in animal models and contribute to decreased lymphoma dissemination in patients. The latter may contribute to the association of HGAL protein expression with longer survival of patients with DLBCL and HL tumors. The ability to regulate multiple and distinct functions simultaneously in B cells implies that the HGAL protein level is tightly regulated. It was demonstrated that HGAL can be regulated by PR/SET domain 1 (PRDM1)/B lymphocyte-induced maturation protein-1 (BLIMP1) and interleukin-4 (IL-4) at the transcription level, by microRNA-155 (miR-155) at the post-transcriptional level, and by F-box protein 10 (FBXO10) at the post-translational level. Constitutive enforced expression of HGAL at physiological levels leads to lymphoid hyperplasia and DLBCL in mice. Future studies need to focus on identifying HGAL interactome, dissecting its interaction network, and understanding HGAL spatiotemporal signaling in live cells in physiological conditions. Further, the recent demonstration of HGAL expression in Tfh cells requires the determination of its function in these cells. These studies will contribute to new insights into the biology of these cellular subsets and how immune dysregulation contributes to lymphomagenesis.
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