Inhibition of a cyclic nucleotide-gated channel on neuronal cilia activates unfolded protein response in intestinal cells to promote longevity.

Abstract

Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of <i>Caenorhabditis elegans</i> neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPR^ER) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPR^ER doesn't alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPR^ER-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPR^ER in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal UPR^ER and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPR^ER, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan.