Universität zu Köln

Huang, Wenming, Kew, Chun, Fernandes, Stephanie de Alcantara, Loehrke, Anna, Han, Lynn, Demetriades, Constantinos ORCID: 0000-0001-7813-7726 and Antebi, Adam (2022). Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity. Nature Aging, 2 (9). S. 796 - 828. LONDON: SPRINGERNATURE. ISSN 2662-8465

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Abstract

RNA splicing has a role in aging and longevity, but the mechanisms involved are incompletely understood. Here the authors show that mRNA splicing components, RNP-6 and RBM-39, act in concert to regulate intron retention, inhibit mTORC1 signaling and prolong life in Caenorhabditis elegans. Changes in splicing fidelity are associated with loss of homeostasis and aging, yet only a handful of splicing factors have been shown to be causally required to promote longevity, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within ribonucleoprotein RNP-6/poly(U)-binding factor 60 kDa (PUF60), a spliceosome component promoting weak 3 '-splice site recognition, which causes aberrant splicing, elevates stress responses and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6-interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover intron retention in egl-8/phospholipase C beta 4 (PLCB4) as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulates mammalian target of rapamycin complex 1 (mTORC1) signaling to control organismal lifespan. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates lifespan through mTOR signaling.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Huang, Wenming UNSPECIFIED UNSPECIFIED UNSPECIFIED Kew, Chun UNSPECIFIED UNSPECIFIED UNSPECIFIED Fernandes, Stephanie de Alcantara UNSPECIFIED UNSPECIFIED UNSPECIFIED Loehrke, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Han, Lynn UNSPECIFIED UNSPECIFIED UNSPECIFIED Demetriades, Constantinos UNSPECIFIED orcid.org/0000-0001-7813-7726 UNSPECIFIED Antebi, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-682299
DOI:	10.1038/s43587-022-00275-z
Journal or Publication Title:	Nature Aging
Volume:	2
Number:	9
Page Range:	S. 796 - 828
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2662-8465
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXTENDS LIFE-SPAN; GENE-EXPRESSION; STEM-CELLS; RNA; BINDING; PUF60; TOR; COLOCALIZATION; TRANSFORMATION; RESTRICTION Multiple languages Cell Biology; Geriatrics & Gerontology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68229