Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling
Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling
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DOI：
10.1016/j.bbamcr.2012.11.009
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发表时间：
2013-03-01
影响因子：
5.1
通讯作者：
Peiretti, Franck
中科院分区：
文献类型：
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作者：
Poggi, Marjorie;Kara, Imene;Peiretti, Franck
多效性促炎细胞因子肿瘤坏死因子α（TNF）是作为一种跨膜蛋白合成的，经过棕榈酰化。在这项研究中，这种酰化作用对TNF介导的生物学效应进行了研究。我们发现TNF的脂筏分配受其棕榈酰化的调节。此外，我们证明了棕榈酰化过程干扰TNF细胞内片段的切割/降解，但不参与其胞外域脱落的调节。此外，我们发现TNF的棕榈酰化阻碍了可溶性TNF与TNFR 1的结合，并调节TNFR 1整合/保留到脂筏中。最后，我们证明了跨膜形式的野生型和棕榈酰化缺陷的TNF与TNFR 1的相互作用不同，并调节NF κ B B活性，Erk 1/2磷酸化和白细胞介素6的合成不同，强烈表明TNF的棕榈酰化参与调节TNFR 1信号。在巨噬细胞中，内源性可溶性TNF与TNFR 1的结合通过抑制棕榈酰化而增强，这一事实提供了这种调节的生理干预的证据。因此，我们的数据介绍了新的概念，棕榈酰化的TNF是TNF产生细胞调节其敏感性可溶性TNF的手段之一。(C)2012爱思唯尔有限公司版权所有。
The pleiotropic pro-inflammatory cytokine tumour necrosis factor alpha (TNF) is synthesised as a transmembrane protein that is subject to palmitoylation. In this study, the roles of this acylation on TNF-mediated biological effects were investigated. We found that the lipid raft partitioning of TNF is regulated by its palmitoylation. Furthermore, we demonstrated that this palmitoylation process interferes with the cleavage/degradation of TNF intracellular fragments but is not involved in the regulation of its ectodomain shedding. Moreover, we found that the palmitoylation of TNF hinders the binding of soluble TNF to TNFR1 and regulates the integration/retention of TNFR1 into lipid rafts. Finally, we demonstrate that the transmembrane forms of wild-type and palmitoylation-defective TNF interact differently with TNFR1 and regulate NF kappa B activity, Erk1/2 phosphorylation and interleukin-6 synthesis differently, strongly suggesting that palmitoylation of TNF is involved in the regulation of TNFR1 signalling. An evidence for the physiological intervention of this regulation is provided by the fact that in macrophages, the binding of endogenous soluble TNF to TNFR1 is enhanced by inhibition of palmitoylation. Therefore, our data introduce the new concept that palmitoylation of TNF is one of the means by which TNF-producing cells regulate their sensitivity to soluble TNF. (C) 2012 Elsevier B.V. All rights reserved.