Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis
Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis
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自我抑制的破坏是 ASIC1a 构象信号传导诱导神经元坏死性凋亡的基础
DOI：
10.1038/s41467-019-13873-0
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发表时间：
2020-01-24
影响因子：
16.6
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
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作者：
Wang, Jing-Jing;Liu, Fan;Xu, Tian-Le
我们之前报道过酸感离子通道1a （ASIC1a）通过将受体相互作用蛋白激酶1 （RIPK1）募集到其C端（CT）介导酸性神经元坏死，而不依赖于其离子传导功能。在这里，我们发现ASIC1a的n端（NT）与其CT相互作用形成自抑制，在静息条件下阻止RIPK1的募集/激活。这种相互作用涉及远端NT的谷氨酸残基，并因酸中毒而中断。突变体ASIC1a在远端NT上的截断或谷氨酸-丙氨酸取代的表达导致了组成性细胞死亡。n -乙基酰亚胺敏感融合atp酶（NSF）进一步破坏NT-CT的相互作用，NSF在酸中毒时与ASIC1a-NT相关，促进RIPK1与ASIC1a-CT的相互作用。重要的是，一种代表远端20个ASIC1a NT残基的穿膜合成肽NT1-20，在体外酸毒性模型和小鼠体内缺血性中风模型中都减少了神经元损伤，证明了靶向ASIC1a自身抑制神经保护抗酸毒性的治疗潜力。
We reported previously that acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1) to its C terminus (CT), independent of its ion-conducting function. Here we show that the N-terminus (NT) of ASIC1a interacts with its CT to form an auto-inhibition that prevents RIPK1 recruitment/activation under resting conditions. The interaction involves glutamate residues at distal NT and is disrupted by acidosis. Expression of mutant ASIC1a bearing truncation or glutamate-to-alanine substitutions at distal NT causes constitutive cell death. The NT-CT interaction is further disrupted by N-ethylmaleimide-sensitive fusion ATPase (NSF), which associates with ASIC1a-NT under acidosis, facilitating RIPK1 interaction with ASIC1a-CT. Importantly, a membrane-penetrating synthetic peptide representing the distal 20 ASIC1a NT residues, NT1–20, reduced neuronal damage in both in vitro model of acidotoxicity and in vivo mouse model of ischemic stroke, demonstrating the therapeutic potential of targeting the auto-inhibition of ASIC1a for neuroprotection against acidotoxicity.