HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity

Cell. 2012 Jan 20;148(1-2):322-34. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Heat-Shock Proteins / metabolism
  • Longevity*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Receptor, Insulin / metabolism
  • Signal Transduction*
  • Somatomedins / metabolism*
  • Transcription Factors / metabolism*


  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • DDL-1 protein, C elegans
  • DDL-2 protein, C elegans
  • Heat-Shock Proteins
  • Phosphoproteins
  • Somatomedins
  • Transcription Factors
  • heat shock factor-1, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin