The teneurin TEN-1 and its ligand LRON-11 support microbiota-induced neuroprotection and mechanosensory function in C. elegans.

Abstract

Neuroprotection preserves neuronal structure and function by limiting damage and cell death, and diet-associated microbiota produce metabolites capable of influencing neuronal survival.^1,2,3 In C. elegans, GABA and lactate produced by E. coli HT115 protect touch receptor neurons (TRNs) from MEC-4(d)-induced degeneration,² and comparative gene-expression analysis identified the teneurin ten-1 as required for this microbiota-induced neuroprotection.³ Teneurins are evolutionarily conserved cell-adhesion molecules that regulate nervous system development, axon guidance, synapse formation, and neuronal connectivity primarily through trans-cellular interactions,^{4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22} and C. elegans, which contains a single teneurin gene, requires TEN-1 for normal nervous system development and tissue organization.^5,13,14,23 Although vertebrate teneurins bind latrophilin G protein-coupled receptors,^17,21,22,24 the C. elegans latrophilin homolog LAT-1 acts in parallel to TEN-1,²⁵ leaving the receptor-ligand interactions that underlie TEN-1 function incompletely understood. Here, we identify Leucine-Rich Repeat Only 11 (LRON-11), a previously uncharacterized cell-adhesion molecule, as the ligand for TEN-1. The high-resolution cryoelectron microscopy (cryo-EM) structure of the TEN-1-LRON-11 complex reveals that the leucine-rich repeat domain of LRON-11 directly engages the transthyretin (TTR) domain of TEN-1 through a previously unrecognized interaction interface. Tissue-specific genetic analyses demonstrate that TEN-1 and LRON-11 are required for microbiota-mediated neuroprotection, and structure-guided interface mutations disrupting TEN-1-LRON-11 binding impair normal touch responses in vivo. Together, our findings establish a conserved receptor-ligand signaling axis that supports microbiota-mediated neuroprotection and normal touch responses, revealing how a single receptor-ligand interaction can support distinct neuronal functions.