Authors: Chiang WC; Ching TT; Lee HC; Mousigian C; Hsu AL
Abstract: 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.Keywords: Animals; Caenorhabditis elegans/*metabolism; Caenorhabditis elegans Proteins/genetics/*metabolism; Carrier Proteins/genetics/*metabolism; Heat-Shock Proteins/metabolism; *Longevity; Phosphoproteins/genetics/*metabolism; Phosphorylation; Receptor, Insulin/metabolism; *Signal Transduction; Somatomedins/*metabolism; Transcription Factors/*metabolism
Date: Jan. 24, 2012
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Chiang WC, Ching TT, Lee HC, Mousigian C, Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148: 322-34.