Journal Article

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

Qi, Xin, Wang, Yi-Zhi, Li, Ying, Zhu, Michael X., Yang, Fan, Hu, Qin, Wang, Jing-Jing, Xu, Tian-Le, Liu, Fan

2020

Overview

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, NT 1–20 , 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. Acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1). Here authors show that auto-inhibition of ASICa prevents RIPK1 recruitment and demonstrate that targeting the auto-inhibition has therapeutic potential to prevent acidotoxicity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/109 / 13/89 / 14 / 14/19 / 14/33 / 14/35 / 14/63 / 631/378/2586 / 631/57 / 631/80/82/2344 / 82/58 / Acid Sensing Ion Channels - chemistry / Acid Sensing Ion Channels - genetics / Acid Sensing Ion Channels - physiology / Acidosis / Acidosis - pathology / Acidosis - physiopathology / Adenosine triphosphatase / Alanine / Amino Acid Substitution / Animals / Cell death / Disruption / Female / Humanities and Social Sciences / Ion channels / Ischemia / Kinases / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Models, Molecular / Models, Neurological / multidisciplinary / Mutants / N-Ethylmaleimide / N-Ethylmaleimide-Sensitive Proteins - pharmacology / N-Ethylmaleimide-Sensitive Proteins - physiology / N-Terminus / Necroptosis / Necroptosis - physiology / Neurons - cytology / Neurons - physiology / Neuroprotection / Neuroprotection - drug effects / Neuroprotection - physiology / Neurotrophin 1 / Peptide Fragments - chemistry / Peptide Fragments - genetics / Peptide Fragments - physiology / Protein Conformation / Protein Interaction Domains and Motifs / Protein kinase / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinases - physiology / Recruitment / Residues / Science / Science (multidisciplinary) / Signal Transduction / Stroke - pathology / Stroke - physiopathology