A THEMIS:SHP1 complex promotes T-cell survival.
A THEMIS:SHP1 complex promotes T-cell survival.
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DOI：
10.15252/embj.201387725
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发表时间：
2015-02-03
期刊：
影响因子：
--
通讯作者：
Acuto O
中科院分区：
文献类型：
--
作者：
Paster W;Bruger AM;Katsch K;Grégoire C;Roncagalli R;Fu G;Gascoigne NR;Nika K;Cohnen A;Feller SM;Simister PC;Molder KC;Cordoba SP;Dushek O;Malissen B;Acuto O
THEMIS对于传统的T细胞发育至关重要，但其精确的分子功能仍然难以捉摸。在这里，我们表明，THEMIS组成型协会与磷酸酶SHP 1和SHP 2。该复合物需要衔接子GRB 2，其以不依赖于Tyr磷酸化的方式将SHP桥接至THEMIS。相反，SHP 1和THEMIS分别与GRB 2的N-SH 3和C-SH 3结构域接合，这种构型允许GRB 2-SH 2将复合物募集到LAT上。与THEMIS介导的SHP向TCR信号体的募集一致，THEMIS敲低增加了TCR诱导的CD 3-ERK磷酸化、Erk活化和CD 69表达，但不增加LCK磷酸化。这种普遍的TCR信号传导增加导致细胞凋亡增加，这是通过SHP 1敲低反映的表型。值得注意的是，以前被认为是ERK介导的对SHP 1负反馈的抗性的关键的LCK Ser 59的KI突变不影响体内TCR信号传导或配体辨别。因此，THEMIS：SHP复合物通过先前未知的有利于T细胞存活的分子机制抑制早期TCR信号传导。我们讨论了这种机制在调节TCR输出信号对传统的T细胞发育和分化的可能影响。
THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Consistent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knock-down increased TCR-induced CD3-ζ phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock-down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK-mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T-cell development and differentiation.
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