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Updated: May 25, 2026

Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity
Wei-Chung Chiang1, Tsui-Ting Ching, Hee Chul Lee
1Department of Molecular and Integrative Physiology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
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.
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