The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans

Abstract

An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues. The homeodomain-interacting protein kinase (hipk) family members are conserved transcriptional co-factors that have been implicated in both genotoxic and metabolic stress responses from yeast to mammals. We demonstrate that constitutive expression of the sole Caenorhabditis elegans Hipk homolog, hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 is deleterious to these phenotypes. We show that HPK-1 preserves proteostasis and extends longevity through distinct but complementary genetic pathways defined by the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). We demonstrate that HPK-1 antagonizes sumoylation of HSF-1, a post-translational modification associated with reduced transcriptional activity in mammals. We show that inhibition of sumoylation by RNAi enhances HSF-1-dependent transcriptional induction of chaperones in response to heat shock. We find that hpk-1 is required for HSF-1 to induce molecular chaperones after thermal stress and enhances hormetic extension of longevity. We also show that HPK-1 is required in conjunction with HSF-1 for maintenance of proteostasis in the absence of thermal stress, protecting against the formation of polyglutamine (Q35::YFP) protein aggregates and associated locomotory toxicity. These functions of HPK-1/HSF-1 undergo rapid down-regulation once animals reach reproductive maturity. We show that HPK-1 fortifies proteostasis and extends longevity by an additional independent mechanism: induction of autophagy. HPK-1 is necessary for induction of autophagosome formation and autophagy gene expression in response to dietary restriction (DR) or inactivation of TORC1. The autophagy-stimulating transcription factors pha-4/FoxA and mxl-2/Mlx, but not hlh-30/TFEB or the nuclear hormone receptor nhr-62, are necessary for extended longevity resulting from HPK-1 overexpression. HPK-1 expression is itself induced by transcriptional mechanisms after nutritional stress, and post-transcriptional mechanisms in response to thermal stress. Collectively our results position HPK-1 at a central regulatory node upstream of the greater proteostatic network, acting at the transcriptional level by promoting protein folding via chaperone expression, and protein turnover via expression of autophagy genes. HPK-1 therefore provides a promising intervention point for pharmacological agents targeting the protein homeostasis system as a means of preserving robust longevity.

SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

“…HSF-1, SKN-1 and DAF-16 are key stress response transcription factors, promoting longevity under conditions of heat shock, mild oxidative stress and low insulin/IGF1 signalling 8 . Considering, that HSF-1 has been shown to have the potential to be modified by SUMO, both in mammals 48 and in C. elegans 49 , we focused our studies on SKN-1 and DAF-16. We find that skn-1(RNAi);smo-1(RNAi) animals display shorter lifespan, similar to animals subjected only to skn-1 RNAi (Fig.…”

Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy

“…Based on our results, calpain 1 signalling, but not the mTOR pathway, is involved in the HIPK2-mediated increase in autophagic flux. In addition, HPK-1, the sole orthologue of the mammalian HIPK family in Caenorhabditis elegans , is required for the formation of autophagosomes and induction of autophagy-related gene expression after nutrient deprivation or mTOR inactivation 69 . Another orthologue of the human HIPK2 gene, Yak1 kinase in Saccharomyces cerevisiae , is one such target that is negatively regulated by both the PKA and TOR pathways 70 , 71 .…”

TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging

“…Activation of PHA-4/FOXA by let-363/ TOR knockdown has been linked to the kinase GCN-2, which regulates translation, thereby intertwining regulation of translation and autophagy by TOR (Rousakis et al 2013). Additionally, life span extension from knockdown of daf-15/raptor or let-363/TOR depends upon the conserved kinase HPK-1, which is also required for autophagy to be increased when TORC1 signaling is reduced (Das et al 2017). Finally, spermidine induces chromatin modifications that increase life span in yeast, C. elegans, Drosophila, and mice by upregulating autophagy (Eisenberg et al 2009), and in C. elegans overexpression of HLH-30/TFEB on its own extends life span (Lapierre et al 2013).…”