title: HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Chiang
authors.forename: Tsui-Ting
authors.initials: TT
authors.lastname: Ching
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Carol
authors.initials: C
authors.lastname: Mousigian
authors.forename: Ao-Lin
authors.initials: AL
authors.lastname: Hsu
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008136:Longevity; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C570697:DDL-1 protein, C elegans; C570698:DDL-2 protein, C elegans; D006360:Heat-Shock Proteins; D010750:Phosphoproteins; D013002:Somatomedins; D014157:Transcription Factors; C474710:heat shock factor-1, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin