Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins.
Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins.
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白介素 6 受体和肿瘤坏死因子 α 的脱落。
DOI：
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
J. Müllberg
中科院分区：
文献类型：
--
作者：
K. Althoff;P. Reddy;N. Voltz;S. Rose;J. Müllberg
一组功能和结构上不同的跨膜蛋白，包括跨膜形式的介体或受体，可以被蛋白水解酶切割而形成可溶性生长因子或受体。最近，与肿瘤坏死因子α前体(ProTNFpha)加工有关的蛋白分解活性已被鉴定，并命名为TACE(TNFpha转换酶)。在TACE缺陷(TACE-/-)成纤维细胞的实验中，我们发现4β-佛波醇12-肉豆蔻酸酯(PMA)诱导的白介素6受体(IL-6R)脱落明显减少。然而，仍可检测到基础羟氨酸盐敏感的IL-6R释放。这一结果表明，TACE在IL-6R的加工过程中发挥了作用，可能涉及其他金属蛋白酶。稳定转染TACE基因可恢复PMA诱导的IL-6R在TACE缺陷小鼠成纤维细胞中的分泌。为了研究IL-6R和proTNFα脱落之间的差异，我们构建了IL-6R和proTNFα嵌合蛋白，其中内源裂解位点(CS)分别被相应的proTNFα和IL-6R区域所取代。有趣的是，ProTNFpha嵌合蛋白只有很少的脱落。相反，含有proTNFpha CS的IL-6R嵌合体自发脱落，PMA不能进一步诱导加工。因此，通过引入proTNFpha CS而转移的切割模式与proTNFpha本身的切割模式相似。我们得出结论，蛋白质水解区的氨基酸序列对蛋白质的切割特性有贡献。然而，仅有这一信息不足以转移切割能力，如含有IL-6R CS的proTNFpha嵌合体所看到的那样，并且这些嵌合体抵抗脱落。
A functionally and structurally diverse group of transmembrane proteins including transmembrane forms of mediators or receptors can be proteolytically cleaved to form soluble growth factors or receptors. Recently, the proteolytic activity responsible for pro-tumor necrosis factor alpha (proTNFalpha) processing has been identified and named TACE (TNFalpha converting enzyme). In experiments with TACE deficient (TACE-/-) fibroblasts we found that 4beta-phorbol 12-myristate 13-acetate (PMA)-induced shedding of the interleukin-6 receptor (IL-6R) is strongly reduced. A basal hydroxamate sensitive release of IL-6R, however, could still be detected. This result demonstrates that TACE plays a role in IL-6R processing and that additional metalloproteases might be involved. PMA-induced shedding of IL-6R in TACE deficient mouse fibroblasts could be restored by stable transfection of a TACE cDNA. To characterize differences between shedding of IL-6R and proTNFalpha we generated chimeric IL-6R and proTNFalpha proteins wherein the endogenous cleavage sites (CS) had been replaced by the corresponding region of proTNFalpha and IL-6R, respectively. Interestingly, proTNFalpha chimeric proteins showed only minimal shedding. In contrast, IL-6R chimeras containing the proTNFalpha CS were shed spontaneously, processing was not further induced by PMA. Thus, the cleavage pattern transferred by the introduction of the proTNFalpha CS is similar to that of proTNFalpha itself. We conclude that the amino-acid sequence at the proteolytic CS contributes to the cleavage characteristics of a protein. However, this information alone is not sufficient to transfer cleavability as seen with proTNFalpha chimeras containing the IL-6R CS and which were resistant to shedding.
血管紧张素转换酶的远端胞外域调节其从细胞表面的裂解分泌。
DOI：
10.1073/pnas.95.1.138
发表时间：
1998
影响因子：
11.1
作者：
Sadhukhan,R;Sen,GC;Ramchandran,R;Sen,I
通讯作者：
Sen,I
影响因子：
56.9
作者：
Peschon, JJ;Slack, JL;Black, RA
通讯作者：
Black, RA