Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
Sci Signal. 2018 Nov 20;11(557):eaap9921. doi: 10.1126/scisignal.aap9921.
It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)-mediated antiviral response. Here, we found that IFN-γ receptor stimulation also activated Unc-51-like kinase 1 (ULK1), an initiator of Beclin-1-mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ-dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.
众所周知，转录因子信号转导子和转录激活子 1（STAT1）的激活对于干扰素-γ（IFN-γ）介导的抗病毒反应是必需的。在这里，我们发现 IFN-γ 受体刺激也激活了自噬的起始因子 Unc-51 样激酶 1（ULK1）。此外，ULK1 和丝裂原活化蛋白激酶激酶激酶 MLK3（混合谱系激酶 3）之间的相互作用对于 MLK3 的磷酸化和下游激酶 ERK5 的激活是必要的。ULK1 的这种非自噬依赖性活性促进了关键抗病毒干扰素刺激基因（ISGs）的转录，并且对于 IFN-γ 依赖性抗病毒作用是必需的。这些发现定义了一个以前未知的 IFN-γ 途径，它似乎是抗病毒反应的关键组成部分。
