A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1.
A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1.
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DOI：
10.18632/oncotarget.1492
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发表时间：
2014-01-15
期刊：
影响因子：
--
通讯作者：
Lazo PS
中科院分区：
文献类型：
--
作者：
Cabal-Hierro L;Artime N;Iglesias J;Prado MA;Ugarte-Gil L;Casado P;Fernández-García B;Darnay BG;Lazo PS
肿瘤坏死因子（TNF）与两种称为TNFR 1和TNFR 2的受体相互作用。TNFR 1的活化可导致细胞增殖或细胞死亡。TNFR 2激活核因子-kB（NF-kB）和c-Jun N-末端激酶（JNK），其导致与细胞增殖和存活相关的基因的转录激活。这取决于TNF受体相关因子2（TRAF 2）与受体的结合。TNFR 2也诱导TRAF 2降解。在这项工作中，我们研究了负责诱导TRAF 2降解的TNFR 2的结构特征，并研究了这种活性的生物学后果。我们发现，当TNFR 1和TNFR 2共表达时，TRAF 2耗竭导致增强的TNFR 1细胞毒性，这与NF-kB的抑制相关。NF-kB活化和TRAF 2降解取决于受体的不同区域，因为TNFR 2在氨基酸343-349处的突变体不能诱导TRAF 2降解，并且已经失去了它们增强TNFR 1介导的细胞死亡的能力，但仍然能够活化NF-kB。此外，尽管NF-kB激活需要TRAF 2与受体结合，但TRAF 2降解似乎不依赖于TRAF 2结合。因此，不能结合TRAF 2的TNFR 2突变体仍然能够诱导其降解并增强TNFR 1介导的细胞毒性。为了进一步验证这种受体串扰，我们开发了一种在仅携带内源性TNFR 1的细胞中稳定表达嵌合受体RANK-TNFR 2的系统，该系统由RANK（NF-κ B受体激活剂）的胞外区和TNFR 2的胞内区形成，这使得可以独立地研究TNFR 1和TNFR 2触发的信号。在这些细胞中，TNFR 1被可溶性TNF（sTNF）选择性激活，而RANK-TNFR 2被RANKL选择性激活。用sTNF和RANKL处理这些细胞导致增强的细胞毒性。
Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.
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影响因子：
8
作者：
Javelaud, D;Besançon, F
通讯作者：
Besançon, F
DOI：
10.1006/bbrc.2000.2873
发表时间：
2000-06-16
影响因子：
3.1
作者：
Arch, RH;Gedrich, RW;Thompson, CB
通讯作者：
Thompson, CB
DOI：
10.1073/pnas.0806585105
发表时间：
2008-08-26
影响因子：
11.1
作者：
Chen, Nien-Jung;Chio, Iok In Christine;Mak, Tak W.
通讯作者：
Mak, Tak W.
影响因子：
4.8
作者：
Feng, X;Gaeta, ML;Pober, JS
通讯作者：
Pober, JS
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK