Src family kinase tyrosine phosphorylates Toll-like receptor 4 to dissociate MyD88 and Mal/Tirap, suppressing LPS-induced inflammatory responses.
Src family kinase tyrosine phosphorylates Toll-like receptor 4 to dissociate MyD88 and Mal/Tirap, suppressing LPS-induced inflammatory responses.
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DOI：
10.1016/j.bcp.2017.11.015
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发表时间：
2018-01
影响因子：
5.8
通讯作者：
Rhee SH
中科院分区：
文献类型：
--
作者：
Mitchell J;Kim SJ;Seelmann A;Veit B;Shepard B;Im E;Rhee SH
Src家族激酶（SFK）是蛋白酪氨酸激酶家族，包含9个成员：Src、林恩、Fgr、Hck、Lck、Fyn、Blk、Yes和Ylk。虽然SFK激活是LPS/Toll样受体4（TLR 4）信号传导中的主要直接信号传导事件，但由于从某些SFK成员缺陷小鼠或细胞获得的各种矛盾结果，其确切作用仍然难以捉摸。观察到的不一致性可能是由于在SFK缺陷时由其他SFK补偿或冗余。化学拯救方法被建议在活细胞中诱导瞬时和精确的SFK激活，从而限制细胞适应SFK缺陷条件的机会。使用拯救方法，我们证明恢复SFK活性不仅诱导TLR 4的酪氨酸磷酸化，而且抑制LPS诱导的NFκB和JNK 1/2活化，从而抑制LPS诱导的细胞因子产生。TLR 4通常响应于LPS募集含有TIR结构域的衔接子，然而，暂时恢复的SFK活化破坏了LPS诱导的MyD 88和Mal/Tirap与TLR 4的缔合。此外，使用激酶死亡的SFK-Lyn（Y397/508 F）和组成型活性的SFK-Lyn（Y508 F），我们发现激酶死亡的SFK抑制TLR 4酪氨酸磷酸化，与TLR 4的结合亲和力降低，而激酶活性的SFK强烈结合TLR 4并促进TLR 4酪氨酸磷酸化，这表明SFK激酶活性是TLR 4酪氨酸磷酸化和TLR 4-SFK相互作用所必需的。总之，我们的研究结果表明，SFK激活诱导TLR 4酪氨酸磷酸化，从而使MyD 88和Mal/Tirap与TLR 4解离，并抑制LPS诱导的炎症反应，这表明SFK诱导的TLR 4酪氨酸磷酸化调节负反馈环。
Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll-like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member-deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK-deficient condition. Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS-induced NFκB and JNK1/2 activation and consequently suppresses LPS-induced cytokine production. TLR4 normally recruits TIR domain-containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS-induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase-dead SFK-Lyn (Y397/508F) and constitutively active SFK-Lyn (Y508F), we found that the kinase-dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase-active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4-SFK interaction. Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS-induced inflammatory responses, suggesting a negative feedback loop regulated by SFK-induced tyrosine phosphorylation in TLR4.
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影响因子：
4.8
作者：
Medvedev, Andrei E.;Piao, Wenji;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
DOI：
10.1073/pnas.1300617110
发表时间：
2013-08-27
影响因子：
11.1
作者：
Lamagna, Chrystelle;Scapini, Patrizia;Lowell, Clifford A.
通讯作者：
Lowell, Clifford A.
影响因子：
4.8
作者：
Rhee, Sang Hoon;Kim, Ho;Pothoulakis, Charalabos
通讯作者：
Pothoulakis, Charalabos
DOI：
10.4049/jimmunol.0803941
发表时间：
2009-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gross AJ;Lyandres JR;Panigrahi AK;Prak ET;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
3.3
作者：
Borzęcka-Solarz K;Dembińska J;Hromada-Judycka A;Traczyk G;Ciesielska A;Ziemlińska E;Świątkowska A;Kwiatkowska K
通讯作者：
Kwiatkowska K