A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans.
The PTEN tumour suppressor encodes a phosphatase, and its daf-18 orthologue in Caenorhabditis elegans negatively regulates the insulin/IGF-1 DAF-2 receptor pathway that influences lifespan in worms and other species. In order to identify new DAF-18 regulated pathways involved in aging, we initiated a candidate RNAi feeding screen for clones that lengthen lifespan. Here, we report that smg-1 inactivation increases average lifespan in a daf-18 dependent manner. Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO. SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals. In addition, human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress. The effect of smg-1 inactivation on lifespan appears to be unrelated to its NMD function, but requires the p53 tumour suppressor orthologue cep-1. Furthermore, smg-1 inactivation confers a resistance to oxidative stress in a daf-18-, daf-16- and cep-1-dependent manner. We propose that the role of SMG-1 in lifespan regulation is at least partly dependent on its function in oxidative stress resistance. Taken together, our results unveil a novel role for SMG-1 in lifespan regulation.
Masse
Ingrid
I
Laboratoire de Génétique, Signalisation et Cancer, Université Claude Bernard Lyon 1, CNRS UMR5201 Domaine Rockefeller, Lyon, France.
Molin
Laurent
L
Mouchiroud
Laurent
L
Vanhems
Philippe
P
Palladino
Francesca
F
Billaud
Marc
M
Solari
Florence
F
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017238:Genes, Helminth; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference
D029742:Caenorhabditis elegans Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C490966:SMG-1 protein, C elegans