Cell
Volume 148, Issues 1–2, 20 January 2012, Pages 322-334
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Article
HSF-1 Regulators DDL-1/2 Link Insulin-like Signaling to Heat-Shock Responses and Modulation of Longevity

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Summary

Extended longevity is often correlated with increased resistance against various stressors. Insulin/IGF-1-like signaling (IIS) is known to have a conserved role in aging and cellular mechanisms against stress. In C. elegans, genetic studies suggest that heat-shock transcription factor HSF-1 is required for IIS to modulate longevity. Here, we report that the activity of HSF-1 is regulated by IIS. This regulation occurs at an early step of HSF-1 activation via two HSF-1 regulators, DDL-1 and DDL-2. Inhibition of DDL-1/2 increases longevity and thermotolerance in an hsf-1-dependent manner. Furthermore, biochemical analyses suggest that DDL-1/2 negatively regulate HSF-1 activity by forming a protein complex with HSF-1. The formation of this complex (DHIC) is affected by the phosphorylation status of DDL-1. Both the formation of DHIC and the phosphorylation of DDL-1 are controlled by IIS. Our findings point to DDL-1/2 as a link between IIS and the HSF-1 pathway.

Highlights

C. elegans DAF-2 insulin-like signaling negatively regulates HSF-1 activity ► DDL-1 and DDL-2 are negative regulators of HSF-1 ► Formation of a complex containing DDL-1/2 and HSF-1 inhibits HSF-1 activity ► DAF-2 signaling promotes DHIC formation by inhibiting DDL-1 phosphorylation

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These authors contributed equally to this work