Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans

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Camara, Henrique ; Inan, Mehmet Dincer ; Vergani Jr, Carlos A. ; Pinto, Silas ; Knittel, Thiago L. ; Salgueiro, Willian G. ; Tonon-da-Silva, Guilherme ; Ramirez, Juliana ; de Moraes, Diogo ; Braga, Deisi L. ; De-Souza, Evandro A. ; Mori, Marcelo A.

• Tipo de documento: Artigo Científico
• Fonte: Gene; v. 895, p. 11-pg., 2023-11-25.

Resumo

Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans, a similar mechanism is conferred by the systemic RNAi pathway. Members of the Systemic RNA Interference Defective (SID) family act at different steps of cellular RNA uptake and export. The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded (dsRNA)-gated dsRNA channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1, sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan. Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan. We termed this phenomenon Intercellular/Extracellular Systemic RNA imbalance (InExS). (AU)

• Processo FAPESP: 17/01339-2 - Desvendando Mecanismos de Controle da Longevidade por RNAs Móveis
• Beneficiário: Henrique Camara
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/25958-9 - DecAI: iniciativa para decodificar o envelhecimento
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/08354-2 - A ação recíproca do sistema imune e do metabolismo como principal determinante do processo de envelhecimento
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/01184-9 - CAMeLEOm: análise entre espécies dos efeitos metabólicos, na expectativa de vida e ômicas de miméticos de restrição dietética
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/04264-8 - Varredura fenotípica de nematóides C. elegans mutantes para proteínas necessárias para a RNAi sistêmica
• Beneficiário: Henrique Camara
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/01587-1 - Investigação do papel de ALG-1 e seus mecanismos regulatórios na manutenção da vitalidade de Caenorhabditis elegans
• Beneficiário: Carlos Alberto Vergani Junior
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 14/10814-8 - Determinação de fatores que controlam a expressão de Dicer in vivo em C. elegans
• Beneficiário: Evandro Araújo de Souza
• Modalidade de apoio: Bolsas no Brasil - Mestrado