Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing.
Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing.
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DOI：
10.1371/journal.pgen.1003855
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发表时间：
2013-10
期刊：
影响因子：
4.5
通讯作者：
Alper S
中科院分区：
文献类型：
--
作者：
De Arras L;Alper S
控制传染病而不诱发不必要的炎症性疾病需要对先天免疫反应进行适当的调节。因此，在感染期间需要激活先天免疫，但必须限制以防止损害。为了实现这一目标，先天免疫的负调节因子限制了应答。在这里，我们研究了一个由MyD88的另一种剪接形式编码的负调控子。MyD88 mRNA以两种可选的剪接形式存在：MyD88L，一种长剪接形式，编码一种通过转导toll样受体（TLR）信号激活先天免疫的蛋白质；另一种是编码另一种抑制反应的蛋白质MyD88S的简短形式。我们发现MyD88S水平调节小鼠巨噬细胞炎症细胞因子产生的程度。MyD88S mRNA水平受SF3A和SF3B mRNA剪接复合体的调控，这些mRNA剪接复合体与TLR信号一起调节MyD88S的产生。因此，SF3A mRNA剪接复合体控制TLR信号负调节因子的产生，从而限制先天免疫激活的程度。作为对感染的反应，身体诱导炎症过程，这对对抗病原体至关重要。然而，严格调节这种炎症反应也是至关重要的，因为过度活跃或慢性激活的炎症会导致无数的疾病，包括败血症、动脉粥样硬化、癌症和克罗恩病。许多基因已经被确定，要么在感染时开启炎症反应（积极调节因子），要么关闭反应以确保其受到限制（消极调节因子）。了解这些负调节因子的作用可能会为限制炎症和预防炎症性疾病的新疗法打开大门。在目前的研究中，我们研究了一种名为MyD88S的负调节因子。我们提供了一个框架来理解MyD88S是如何产生的，身体对感染的反应是如何改变它的产生的，以及它是如何被操纵的，这可能为一些炎症性疾病提供一种新的攻击手段。
Controlling infectious disease without inducing unwanted inflammatory disease requires proper regulation of the innate immune response. Thus, innate immunity needs to be activated when needed during an infection, but must be limited to prevent damage. To accomplish this, negative regulators of innate immunity limit the response. Here we investigate one such negative regulator encoded by an alternative splice form of MyD88. MyD88 mRNA exists in two alternative splice forms: MyD88L, a long form that encodes a protein that activates innate immunity by transducing Toll-like receptor (TLR) signals; and a short form that encodes a different protein, MyD88S, that inhibits the response. We find that MyD88S levels regulate the extent of inflammatory cytokine production in murine macrophages. MyD88S mRNA levels are regulated by the SF3A and SF3B mRNA splicing complexes, and these mRNA splicing complexes function with TLR signaling to regulate MyD88S production. Thus, the SF3A mRNA splicing complex controls production of a negative regulator of TLR signaling that limits the extent of innate immune activation. In response to infection, the body induces the process of inflammation, which is critical to combating the pathogen. However, it also is critical that this inflammatory response be tightly regulated, because overactive or chronically activated inflammation can contribute to a myriad of diseases including sepsis, atherosclerosis, cancer, and Crohn's Disease. Many genes have been identified that either turn on inflammation in response to infection (positive regulators) or turn off the response to ensure that it is limited (negative regulators). Understanding how these negative regulators act may open the door to new therapies to limit inflammation and prevent inflammatory diseases. In the current study, we investigate one such negative regulator called MyD88S. We provide a framework to understand how MyD88S is produced, how the body's response to infection alters its production, and how it might be manipulated, which could provide a new means of attack for some of these inflammatory diseases.
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影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
0.7
作者：
An, Min;Henion, Paul D.
通讯作者：
Henion, Paul D.
影响因子：
56.9
作者：
Aliprantis, AO;Yang, RB;Zychlinsky, A
通讯作者：
Zychlinsky, A
抑制白介素1受体/TOLL样受体信号传导通过剪接的短形式的MyD88抑制是由于其未能募集IRAK-4所致。
影响因子：
15.3
作者：
Burns, K;Janssens, S;Brissoni, B;Olivos, N;Beyaert, R;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
20.3
作者：
Damm, Frederik;Kosmider, Olivier;Fontenay, Michaela
通讯作者：
Fontenay, Michaela