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

• Published in: Nature communications Vol. 11; no. 1; pp. 475 - 12
• Main Authors: Wang, Jing-Jing, Liu, Fan, Yang, Fan, Wang, Yi-Zhi, Qi, Xin, Li, Ying, Hu, Qin, Zhu, Michael X., Xu, Tian-Le
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13873-0

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.