HSF-1 Regulators DDL-1/2 Link Insulin-like Signaling to Heat-Shock Responses and Modulation of Longevity

• Published in: Cell 2012-01, Vol.148 (1-2), p.322-334
• Main Authors: Chiang, Wei-Chung, Ching, Tsui-Ting, Lee, Hee Chul, Mousigian, Carol, Hsu, Ao-Lin
• Format: Article
• Language: English
• Subjects: Animals; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; heat shock response; heat tolerance; Heat-Shock Proteins - metabolism; Longevity; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Receptor, Insulin - metabolism; Signal Transduction; Somatomedins - metabolism; transcription factors; Transcription Factors - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.12.019

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. [Display omitted] ► 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 The insulin-like signaling pathway, which controls longevity in C. elegans, activates the heat-shock transcription factor HSF-1 by disrupting its interaction with its negative regulators, DDL-1 and DDL-2. The findings establish a molecular link between longevity and stress response.