Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
Quadram Institute Bioscience, Norwich Research Park, Norwich, NR4 7UQ, UK.
Nat Commun. 2020 Nov 20;11(1):5919. doi: 10.1038/s41467-020-19670-4.
ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators.
ATG16L1 是一种自噬介体，可指定 LC3 脂质化的部位，其 C 端结构域由 7 个 WD40 重复组成（WD40 结构域，WDD），但其功能尚不清楚。本研究显示，WDD 与细胞因子受体的细胞内结构域相互作用，以调节它们在配体刺激下的信号输出。使用先前描述的 WDD 结合氨基酸基序的改进版本，本研究显示该元件存在于细胞因子受体的细胞内结构域中。其中两个受体，IL-10RB 和 IL-2Rγ，通过该基序识别 WDD，并表现出依赖于 WDD 的 LC3 脂质化活性。IL-10 通过 WDD 促进 IL-10RB/ATG16L1 相互作用，由于内吞作用延迟和 IL10/IL-10R 复合物的早期转运效率低下，缺乏 WDD 的细胞中 IL-10 信号转导作用不佳。本研究数据揭示了 ATG16L1 在细胞因子受体运输和信号转导调控中的 WDD 依赖性作用，并提供了一个 WDD 结合基序，可能用于识别其他 WDD 激活剂。
