Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis

Jing-Jing Wang, Fan Liu, Fan Yang, Yi-Zhi Wang, Xin Qi, Ying Li, Qin Hu (), Michael X. Zhu () and Tian-Le Xu ()
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Jing-Jing Wang: Shanghai Jiao Tong University School of Medicine
Fan Liu: Shanghai Jiao Tong University School of Medicine
Fan Yang: Zhejiang University School of Medicine
Yi-Zhi Wang: Shanghai Jiao Tong University School of Medicine
Xin Qi: Shanghai Jiao Tong University School of Medicine
Ying Li: Shanghai Jiao Tong University School of Medicine
Qin Hu: Shanghai Jiao Tong University School of Medicine
Michael X. Zhu: The University of Texas Health Science Center at Houston
Tian-Le Xu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-13873-0

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