Liao Yi-Hua, Wu June-Tai, Hsieh I-Chun, Lee Hsiu-Hsiang, Huang Pei-Hsin
Department of Dermatology, College of Medicine, National Taiwan University and National Taiwan University Hospital, Taipei 100, Taiwan.
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
iScience. 2023 Jan 18;26(2):106005. doi: 10.1016/j.isci.2023.106005. eCollection 2023 Feb 17.
Ankyrin repeat-rich membrane spanning (ARMS) plays roles in neural development, neuropathies, and tumor formation. Such pleiotropic function of ARMS is often attributed to diverse ARMS-interacting molecules in different cell context. However, it might be achieved by ARMS' effect on global biological mediator like reactive oxygen species (ROS). We established -knockdown in melanoma cells (si) and in eyes ( ) and challenged them with HO. Decreased ARMS in both systems compromises nuclear translocation of NF-κB and induces ROS, which in turn augments autophagy flux and confers susceptibility to HO-triggered autophagic cell death. Resuming NF-κB activity or reducing ROS by antioxidants in si cells and fly decreases intracellular peroxides level concurrent with reduced autophagy and attenuated cell death. Conversely, blocking NF-κB activity in wild-type flies/melanoma enhances ROS and induces autophagy with cell death. We thus uncover intracellular ROS modulated by ARMS-NFκB signaling primes autophagy for autophagic cell death upon oxidative stress.
富含锚蛋白重复序列的跨膜蛋白（ARMS）在神经发育、神经病变和肿瘤形成中发挥作用。ARMS的这种多效性功能通常归因于不同细胞环境中与ARMS相互作用的多种分子。然而，它可能是通过ARMS对活性氧（ROS）等全局生物介质的影响来实现的。我们在黑色素瘤细胞（si）和果蝇眼睛（）中建立了ARMS基因敲低，并对它们进行过氧化氢（HO）刺激。两个系统中ARMS的减少都会损害核因子κB（NF-κB）的核转位并诱导ROS，进而增强自噬通量并导致对HO触发的自噬性细胞死亡的易感性。在si细胞和果蝇中通过抗氧化剂恢复NF-κB活性或减少ROS，可降低细胞内过氧化物水平，同时减少自噬并减轻细胞死亡。相反，在野生型果蝇/黑色素瘤中阻断NF-κB活性会增强ROS并诱导自噬和细胞死亡。因此，我们发现由ARMS-NFκB信号传导调节的细胞内ROS在氧化应激时引发自噬以导致自噬性细胞死亡。
