Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY 11794.
Genentech, San Francisco, CA 94080.
Crit Rev Immunol. 2024;44(1):55-77. doi: 10.1615/CritRevImmunol.2023049638.
The role of FasL in initiating death signals through Fas is well characterized. However, the reverse signaling pathway downstream of FasL in effector lymphocytes is poorly understood. Here, we identify that FasL functions as an independent activation receptor in NK cells. Activation via FasL results in the production of LFN-γ, GM-CSF, RANTES, MIP-1α, and MIP1-β. Proximal signaling of FasL requires Lck and Fyn. Upon activation, FasL facilitates the phosphorylation of PI(3)K-p85α/p55α subunits. A catalytically inactive PI(3)K-p110δD910A mutation significantly impairs the cytokine and chemokine production by FasL. Activation of ITK and LAT downstream of FasL plays a central role in recruiting and phosphorylating PLC-γ2. Importantly, Fyn-mediated recruitment of ADAP links FasL to the Carmal/ Bcl10/Tak1 signalosome. Lack of Carma1, CARD domain of Carma1, or Tak1 significantly reduces FasL-mediated cytokine and chemokine production. These findings, for the first time, provide a detailed molecular blueprint that defines FasL-mediated reverse signaling.
FasL 通过 Fas 启动死亡信号的作用已得到充分描述。然而，FasL 在效应淋巴细胞下游的反向信号通路知之甚少。在这里，我们确定 FasL 在 NK 细胞中作为独立的激活受体发挥作用。通过 FasL 的激活导致产生 LFN-γ、GM-CSF、RANTES、MIP-1α 和 MIP1-β。FasL 的近端信号需要 Lck 和 Fyn。激活后，FasL 促进 PI(3)K-p85α/p55α 亚基的磷酸化。催化失活的 PI(3)K-p110δD910A 突变显著损害 FasL 产生细胞因子和趋化因子的能力。FasL 下游的 ITK 和 LAT 的激活在募集和磷酸化 PLC-γ2 中起核心作用。重要的是，Fyn 介导的 ADAP 募集将 FasL 与 Carmal/Bcl10/Tak1 信号体连接起来。Carmal1 缺失、Carmal1 的 CARD 结构域缺失或 Tak1 显著减少 FasL 介导的细胞因子和趋化因子的产生。这些发现首次提供了一个详细的分子蓝图，定义了 FasL 介导的反向信号。
