Revisiting the secretion mechanism(s) of macrophage migration inhibitory factor—welcome to the “UPS club”
Revisiting the secretion mechanism(s) of macrophage migration inhibitory factor—welcome to the “UPS club”
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重温巨噬细胞迁移抑制因子的分泌机制——欢迎加入“UPS俱乐部”
DOI：
10.1111/imcb.12388
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发表时间：
2020
影响因子：
4
通讯作者：
J. Bernhagen
中科院分区：
文献类型：
--
作者：
A. Hoffmann;J. Bernhagen
细胞因子是调节细胞间通讯的蛋白质介质。它们协调免疫反应，并在许多疾病中发挥关键作用，如炎症和自身免疫性疾病、心血管疾病和癌症。因此，了解它们的表达和分泌机制对于确定阻断致病性细胞因子释放的治疗策略非常重要和有条件。大多数细胞因子携带一种终端信号肽，并通过传统的内质网-高尔基体途径分泌。然而，一些重要的炎症介质，包括白细胞介素(IL)-1细胞因子家族，不表达信号肽，并通过其他途径释放，统称为非常规蛋白分泌（UPS）。巨噬细胞迁移抑制因子（Macrophage migration-inhibitory factor， MIF）是最早发现的细胞因子之一。它是先天免疫的关键上游调节因子和重要的宿主防御蛋白，而失调的MIF是急慢性炎症、动脉粥样硬化、类风湿关节炎和系统性红斑狼疮（SLE）的关键介质。MIF是一种“非典型”细胞因子；这一概念不仅涉及其在不同王国之间的高度进化保守性，还涉及其分子特征，如n端变异体酶口袋，其趋化因子样行为和CXC趋化因子受体的参与，缺乏信号肽和丰富的细胞质表达，以及可能的其他细胞内功能。事实上，此前曾有人提出MIF通过非常规的蛋白分泌途径释放，但缺乏最终证据，其确切机制仍未完全了解。Dankers等人的这项研究为其分泌机制增加了一个重要的新方面，将MIF释放与坏死坏死和核苷酸结合结构域、富含亮氨酸重复序列（NLR）家族pyrin结构域3 （NLRP3）炎性小体依赖性焦亡的过程联系起来。这些数据有助于将MIF确定为“非常规蛋白质分泌UPS蛋白质俱乐部”的成员。MIF是作为t细胞和巨噬细胞细胞因子被发现的，但现在很清楚，它在大多数细胞类型中广泛表达。丰富的MIF细胞质储存池和基线（非病理性）循环MIF水平在1 - 10 ng mL 1范围内被认为是其非典型细胞因子谱的一部分。在炎症条件下，循环中的MIF水平迅速急剧增加，达到500-1500 ng mL的水平。疾病条件下释放的MIF蛋白的实际局部组织水平尚不清楚，但基于体外细胞培养的研究表明，类似的升高率高达10到100倍。虽然MIF的分泌研究主要是在免疫细胞中进行的，但已经清楚的是，在内皮细胞和血小板、实质细胞（如心肌细胞、血管平滑肌细胞和成纤维细胞）以及肿瘤细胞的各种刺激下，MIF的分泌也可能发生。MIF释放上调的机制是非常规的，与内质网/高尔基体无关，最初是由于MIF序列中缺乏信号肽而暗示的，并通过使用经典内质网/高尔基体途径抑制剂的研究得到了实验证明。蛋白质相互作用研究和药理学抑制剂的应用涉及ABC转运蛋白ABCA1、信号小体亚基JAB1/CSN5和细胞质高尔基相关蛋白p115在MIF的非常规蛋白质分泌途径中的作用。JAB1/CSN5被认为具有隔离功能，p115促进MIF通信[J] urgen Bernhagen，血管生物学主席，中风和痴呆研究所（ISD）， LMU大学医院，Ludwig-Maximilians-University (LMU), 81377 Munich, Germany。电子邮件:juergen.bernhagen@med.unimuenchen.de
Cytokines are protein mediators regulating intercellular communication. They orchestrate the immune response and play pivotal roles in numerous diseases such as inflammatory and autoimmune diseases, cardiovascular conditions and cancer. Understanding their expression and secretion mechanisms therefore is important and conditional to the identification of therapeutic strategies blocking the release of pathogenic cytokines. Most cytokines carry an Nterminal signal peptide and are secreted via the conventional endoplasmic reticulum (ER)-Golgi route. However, a number of important inflammatory mediators including the interleukin (IL)-1 family of cytokines do not express a signal peptide and are released by alternative pathways, collectively termed unconventional protein secretion (UPS). Macrophage migration-inhibitory factor (MIF) is one of the oldest cytokines discovered. It is a key upstream regulator of innate immunity and an important host defense protein, whereas dysregulated MIF is a pivotal mediator of acute and chronic inflammatory conditions, atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE). MIF is an “atypical” cytokine; this notion refers not only to its high evolutionary conservation across kingdoms, but also to molecular characteristics such as an N-terminal tautomerase pocket, its chemokine-like behavior and engagement of CXC chemokine receptors, lack of a signal peptide and abundant cytosolic expression as well as presumed additional intracellular functions. In fact, MIF was suggested to be released by unconventional protein secretion routes previously, but ultimate evidence has been missing and the precise mechanisms have remained incompletely understood. This study by Dankers et al. adds an important new facet to its secretion mechanism, linking MIF release to the processes of necroptosis and nucleotide-binding domain, leucine-rich-repeat-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome-dependent pyroptosis. The data contribute to establish MIF as a member of the “unconventional protein secretion UPS club of proteins.” MIF was discovered as a T-cell and macrophage cytokine, but it is now clear that it is broadly expressed in most cell types. Abundant cytosolic storage pools of MIF and baseline (nonpathologic) circulating MIF levels in the 1–10 ng mL 1 range are considered to be part of its atypical cytokine profile. Under inflammatory conditions, circulating MIF levels are rapidly and drastically increased, reaching levels up to 500–1500 ng mL . The actual local tissue levels of released MIF protein under disease conditions are poorly defined, but in vitro cell culture-based studies suggest a similar rate of elevation by up to several 10to 100-fold. While MIF secretion studies have mainly been performed in immune cells, it has become clear that secretion can also occur in response to a variety of stimuli from endothelial cells and platelets, parenchymal cells such as cardiomyocytes, vascular smooth muscle cells and fibroblasts as well as tumor cells. That the mechanism(s) underlying the upregulation of MIF release is unconventional and endoplasmic reticulum/Golgi independent was initially insinuated by the lack of a signal peptide in the MIF sequence and was experimentally demonstrated by studies using inhibitors of the classical ER/Golgi pathway. Protein interaction studies and the application of pharmacological inhibitors implicated the ABC transporter ABCA1, the signalosome subunit JAB1/CSN5 and the cytosolic, Golgiassociated protein p115 in the unconventional protein secretion route of MIF. JAB1/CSN5 has been suggested to have a sequestration function and p115 facilitates MIF Correspondence J€ urgen Bernhagen, Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany. E-mail: juergen.bernhagen@med.unimuenchen.de
DOI：
10.1073/pnas.86.19.7522
发表时间：
1989-10-01
影响因子：
11.1
作者：
WEISER, WY;TEMPLE, PA;DAVID, JR
通讯作者：
DAVID, JR
加油动物：凋亡的效应因子。
影响因子：
19
作者：
Kovacs SB;Miao EA
通讯作者：
Miao EA
影响因子：
17.1
作者：
Stoppe, Christian;Averdunk, Luisa;Boor, Peter
通讯作者：
Boor, Peter