Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain
Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain
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DOI：
10.1016/j.bbrc.2005.01.140
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发表时间：
2005-04-01
影响因子：
3.1
通讯作者：
Adam, D
中科院分区：
文献类型：
--
作者：
Csehi, SB;Mathieu, S;Adam, D
肿瘤坏死因子（TNF）通过与55 kDa结合而导致胰岛素抵抗。TNF受体（TNF-R55），导致蛋白质如胰岛素受体（IR）底物（IRS）-1的丝氨酸磷酸化，随后通过IR减少IRS-1的酪氨酸磷酸化，从而减少IR信号转导。通过独立的受体结构域，TNF-R55激活中性（N-SMase）和酸性鞘磷脂酶（A-SMase），两者都产生鞘脂神经酰胺。已经鉴定了多种候选激酶，其响应于TNF或神经酰胺而使IRS-1丝氨酸磷酸化。然而，由于TNF-R55介导IR抑制的受体结构域尚未被定位，目前尚不清楚TNF是否在N-SMase或A-SMase的参与下发挥这些作用。在这里，我们确定的死亡结构域的TNF-R55负责抑制作用的TNF对IRS- 1的酪氨酸磷酸化，暗示神经酰胺产生的A-SMase作为抑制IR信号的下游介质。(C)2005年爱思唯尔公司所有的Riahts保留。
Tumor necrosis factor (TNF) contributes to insulin resistance by binding to the 55 kDa. TNF receptor (TNF-R55), resulting in serine phosphorylation of proteins such as insulin receptor (IR) substrate (IRS)-1, followed by reduced tyrosine phosphorylation of IRS-1 through the IR and, thereby, diminished IR signal transduction. Through independent receptor domains, TNF-R55 activates a neutral (N-SMase) and an acid sphingomyelinase (A-SMase), that both generate the sphingolipid ceramide. Multiple candidate kinases have been identified that serine-phosphorylate IRS-1 in response to TNF or ceramide. However, due to the fact that the receptor domain of TNF-R55 mediating inhibition of the IR has not been mapped, it is currently unknown whether TNF exerts these effects with participation of N-SMase or A-SMase. Here, we identify the death domain of TNF-R55 as responsible for the inhibitory effects of TNF on tyrosine phosphorylation of IRS- 1, implicating ceramide generated by A-SMase as a downstream mediator of inhibition of IR signaling. (C) 2005 Elsevier Inc. All riahts reserved.