ABSTRACT

The mammalian ULK1 is the central initiating kinase of bulk and selective macroautophagy/autophagy processes. In the past, both autophagy-relevant and non-autophagy-relevant substrates of this Ser/Thr kinase have been reported. Here, we describe our recent finding that ULK1 also regulates TNF signaling pathways. We find that inhibition of autophagy or specifically ULK1 increases TNF-induced cell death. This autophagy-independent pro-survival function of ULK1 is mediated via the phosphorylation of RIPK1 at Ser357. RIPK1 is the central mediator of pro-inflammatory or pro-death signaling pathways induced by TNF, and ULK1-dependent phosphorylation regulates RIPK1 activation and distribution to different intracellular signaling complexes. Our results indicate that ULK1 exerts a cyto-protective function not only by initiating autophagy, but also by controlling RIPK1-mediated cell death.

摘要

哺乳动物ULK1是大量和选择性的巨自噬/自噬过程的中心启动激酶。在过去，已经报道了该Ser / Thr激酶的自噬相关底物和非自噬相关底物。在这里，我们描述了我们最近的发现，即ULK1也调节TNF信号通路。我们发现抑制自噬或特别是ULK1增加TNF诱导的细胞死亡。ULK1的这种自噬独立的生存功能是通过SIP357上RIPK1的磷酸化介导的。RIPK1是TNF诱导的促炎或死亡信号通路的主要介质，而ULK1依赖性磷酸化调节RIPK1的活化和向不同细胞内信号复合物的分布。我们的结果表明，ULK1不仅通过启动自噬来发挥细胞保护功能，