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Light-activated tetanus neurotoxin for conditional proteolysis and inducible synaptic inhibition in vivo
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DOI：10.1038/s41592-026-03176-w.png)
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Abstract
En 中文
The light chain of tetanus neurotoxin (TeNT) is a metalloprotease that potently inhibits synaptic transmission by cleaving the endogenous vesicle fusion protein VAMP2, but its constitutive activity prevents spatiotemporal precision. To address this, we engineered light-activated TeNT (LATeNT) by inserting the light-sensitive LOV domain into an allosteric site and optimizing dynamic range via directed evolution. LATeNT’s activity is undetectable in the dark, but the protease turns on after 10–20 min of weak blue-light exposure to potently inhibit synapses in vivo. Here we show that LATeNT works across multiple brain regions and at long-range axonal projections, with its effects reversible in 24 h. LATeNT enabled us to discover a hippocampal interneuron population that regulates anxiety-like behaviors and demonstrate the importance of postsynaptic endocannabinoid exocytosis for depolarization-induced suppression of inhibition in vivo. Beyond neuroscience, LATeNT regulated endogenous insulin secretion from pancreatic beta cells and converted drug exposure, elevated Ca2+ or receptor activation into transgene expression or reporter secretion in HEK293T cells. With a large dynamic range, high light sensitivity and sustained effect, LATeNT enables versatile, spatiotemporally resolved proteolysis across diverse biological systems. LATeNT is a light-activatable form of tetanus neurotoxin that can be used for spatiotemporally precise inhibition of exocytosis in neurons and other cells. It can inhibit synaptic transmission in vivo or abolish endogenous insulin secretion in pancreatic beta cells in a light-dependent manner, in addition to other applications.
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