Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides

Article

关键词: NEUROTRANSMITTER RELEASE;    MOLECULAR-MECHANISMS;    MUCIN SECRETION;    MUNC13;    MEMBRANE;    VIRUS;    SNARE;    EXOCYTOSIS;    SYSTEM;    MUCUS;   

DOI  :  10.1038/s41586-022-04543-1

来源: SCIE

【 摘 要 】

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes(1-4). For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex', and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion'. Disruption of Ca2+ ttriggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratoryviral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis(7-)(11). Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMPS, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+ ttriggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptidesto the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.

【 授权许可】

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