Differential alternative splicing coupled to nonsense-mediated decay of mRNA ensures dietary restriction-induced longevity

Syed Shamsh Tabrez, Ravi Datta Sharma, Vaibhav Jain, Atif Ahmed Siddiqui and Arnab Mukhopadhyay ()
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Syed Shamsh Tabrez: National Institute of Immunology
Ravi Datta Sharma: Amity University Haryana
Vaibhav Jain: National Institute of Immunology
Atif Ahmed Siddiqui: National Institute of Immunology
Arnab Mukhopadhyay: National Institute of Immunology

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation. Here we show that, during dietary restriction (DR), AS is enhanced in Caenorhabditis elegans and mice. A splicing mediator hrpu-1 regulates a significant part of these AS events in C. elegans; knocking it down suppresses DR-mediated longevity. Concurrently, due to increased AS, NMD pathway genes are upregulated and knocking down UPF1 homologue smg-2 suppresses DR lifespan. Knockdown of NMD during DR significantly increases the inclusion of PTC-containing introns and the lengths of the 3′UTRs. Finally, we demonstrate that PHA-4/FOXA transcriptionally regulates the AS-NMD genes. Our study suggests that DR uses AS to amplify the proteome, supporting physiological remodelling required for enhanced longevity. This increases the dependence on NMD, but also helps fine-tune the expression of metabolic and splicing mediators. AS-NMD may thus provide an energetically favourable level of dynamic gene expression control during dietary restriction.

Date: 2017
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DOI: 10.1038/s41467-017-00370-5

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