Differential Regulation of the Heat Shock Factor 1 and DAF-16 by Neuronal nhl-1 in the Nematode C. elegans

• nhl-1 is a DAF-16 cofactor that is required for stress resistance
• Insulin/IGF-1 signaling regulates nhl-1 expression defining a regulatory circuit
• Neuronal nhl-1 activates DAF-16, but not HSF-1, in remote tissues
• nhl-1 knockdown has no effect on lifespan but protects from proteotoxicity

SummaryIn the nematode Caenorhabditis elegans, insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) reduction hyperactivates the transcription factors DAF-16 and heat shock factor 1 (HSF-1), creating long-lived, stress-resistant worms that are protected from proteotoxicity. How DAF-16 executes its distinct functions in response to IIS reduction is largely obscure. Here, we report that NHL-1, a member of the TRIM-NHL protein family, acts in chemosensory neurons to promote stress resistance in distal tissues by DAF-16 activation but is dispensable for the activation of HSF-1. The expression of nhl-1 is regulated by the IIS, defining a neuronal regulatory circuit that controls the organismal stress response. The knockdown of nhl-1 protects nematodes that express the Alzheimer-disease-associated Aβ peptide from proteotoxicity but has no effect on lifespan. Our findings indicate that DAF-16- and HSF-1-regulated heat-responsive mechanisms are differentially controlled by neurons and show that one neuronal protein can be involved in the activation of different stress responses in remote tissues.

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