HSF-1 Regulators DDL-1/2 Link Insulin-like Signaling to Heat-Shock Responses and Modulation of Longevity

Abstract

Summary 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 might occur 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 regulates 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. Therefore, DDL-1/2 may serve as the link between IIS and HSF-1 pathway.

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

“…The EQ73 worm strain expressing HSF‐1 tagged with GFP under the control of its own endogenous promoter (HSF‐1::GFP) (Chiang, Ching, Lee, Mousigian, & Hsu, 2012) was fed either control RNAi or ccar‐1 RNAi from the L1 larval stage to the L4 larval stage prior to treatment with or without a 15‐min HS. To assess HSF‐1 acetylation, immunoprecipitation of HSF‐1 using an α‐GFP antibody, followed by immunoblotting with an α‐acetylated lysine antibody, was performed (Figure 2a).…”

“…The following C. elegans strains were used in this study: Bristol N2 (wild‐type), sir‐2.1Δ (LG339) (Viswanathan & Tissenbaum, 2013; Viswanathan, Kim, Berdichevsky, & Guarente, 2005), sir‐2.3Δ (RB654) (Barstead & Moerman, 2006), Q35::YFP (AM140) (38), HSF‐1::GFP (EQ73) (Chiang et al, 2012), and the pC12C8.1::GFP reporter strain (39). All strains were grown at 23°C and maintained on standard nematode growth media (NGM) containing the Escherichia coli strain OP50.…”

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

“…All these factors help HSF-1 to play a role in the lifespan extension of the nematode (Kenyon et al 1993;Antebi 2007). However, the activities of the DAF-16 were downregulated by the IIS pathway receptor, DAF-2 by phosphorylating DAF-16 (Henderson and Johnson 2001) and DDL-1 that is required by HSF-1 for its cellular localization (Chiang et al 2012). Since both daf-16 and hsf-1 are important for the lifespan of the nematode, Western blot analysis of hsf-1 was done.…”

Heat Shock and Caloric Restriction Have a Synergistic Effect on the Heat Shock Response in a sir2.1-dependent Manner in Caenorhabditis elegans

“…HSF-1 is responsible for transcriptionally up-regulating the heat shock protein (HSP) genes. In mammalian cells, flies, nematodes, and plants, this transcription factor exists as an inactive monomer; however, in response to denaturing stress, it will trimerize and bind to heat shock elements located in the promoter regions of the hsp genes (3)(4)(5)(6). Increased expression of HSPs, such as HSP70 family members, results in cellular protection from a variety of stressors, including elevated temperatures, oxidative stress, heavy metals, proteasome inhibitors, and infection (7).…”