Mkaddem Sanae Ben, Murua Amaya, Flament Héloise, Titeca-Beauport Dimitri, Bounaix Carine, Danelli Luca, Launay Pierre, Benhamou Marc, Blank Ulrich, Daugas Eric, Charles Nicolas, Monteiro Renato C
INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
CNRS ERL8252, Paris, France.
Nat Commun. 2017 Aug 15;8(1):246. doi: 10.1038/s41467-017-00294-0.
Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling. These SHP-1 signatures are relevant in vivo, as Lyn deficiency exacerbates nephritis and arthritis in mice, whereas Fyn deficiency is protective. Similarly, Fyn-activating signature is detected in patients with lupus nephritis, underlining the importance of this Lyn-Fyn balance. These data show how receptors discriminate negative from positive signals that respectively result in homeostatic or inflammatory conditions.Src-family kinases Fyn and Lyn are signaling components downstream of ITAM-bearing antigen receptors. Here the authors show that by phosphorylating SHP-1 at different residues, Lyn and Fyn can have opposing regulatory effects on ITAM receptors.
免疫受体可根据配体亲和力和磷酸化状态转导抑制性或激活性信号，而这一过程由蛋白激酶Lyn和Fyn调节。在此我们表明，Lyn和Fyn控制免疫受体信号状态。Lyn对SHP-1酪氨酸536的磷酸化激活了磷酸酶，促进通过免疫受体的抑制性信号传导。相比之下，Fyn依赖的SHP-1丝氨酸591磷酸化使磷酸酶失活，从而使激活性免疫受体信号传导成为可能。这些SHP-1特征在体内具有相关性，因为Lyn缺陷会加重小鼠的肾炎和关节炎，而Fyn缺陷则具有保护作用。同样，在狼疮性肾炎患者中检测到Fyn激活特征，突出了这种Lyn-Fyn平衡的重要性。这些数据表明受体如何区分分别导致稳态或炎症状态的负性和正性信号。Src家族激酶Fyn和Lyn是携带免疫受体酪氨酸激活基序（ITAM）的抗原受体下游的信号传导成分。在此，作者表明，通过在不同残基上磷酸化SHP-1，Lyn和Fyn可对ITAM受体产生相反的调节作用。
