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，干扰素-γ（IFN-γ）介导的抗病毒应答需要激活转录因子信号转导子和转录激活子1（STAT1）。在这里，我们发现IFN-γ受体刺激还激活了Beclin-1介导的自噬的启动子Unc-51样激酶1（ULK1）。此外，ULK1和丝裂原活化的蛋白激酶激酶激酶MLK3（混合谱系激酶3）之间的相互作用对于MLK3磷酸化和激酶ERK5的下游活化是必需的。ULK1的这种自噬独立活性促进了关键抗病毒IFN刺激基因（ISG）的转录，对于IFN-γ依赖性抗病毒作用至关重要。这些发现定义了一个以前未知的IFN-γ途径，该途径似乎是抗病毒反应的关键因素。