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

• 成果类型: Article
• 署名作者: Li, Dongdong; Chen, Di; Li, Wei; Ou, Guangshuo
• 署名单位: Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University; Tsinghua University; Zhejiang University; Tsinghua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10010
• DOI: 10.1073/pnas.2321228121
• 发表日期: 2024-06-18
• 关键词: caenorhabditis-elegans; stress resistance; mutations; subunit; PATHWAY; sensor; xbp-1

摘要

Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of Caenorhabditis elegans 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.