Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons
- University of Rochester Medical Center, United States
- University of Rochester, United States
Abstract
Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and GABAergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.
Data availability
Our primary sequence data is available for review (GEO accession GSE220744: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE220744). THE TOKEN FOR REVIEWER ACCESS IS:mzaxakemftsplqvData analysis scripts have been deposited at: https://github.com/samuelsonlab-urmc/hpk1_manuscript_2023All data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for all Figures and Figure supplements in 14 Supplementary Files.
Article and author information
Author details
Maria I Lazaro-Pena
Carlos A Diaz-Balzac
Andrew V Samuelson
Funding
National Institutes of Health (RF1AG062593)
- Maria I Lazaro-Pena
- Adam B Cornwell
- Ritika Das
- Zachary C Ward
- Nicholas Macoretta
- Andrew V Samuelson
National Institutes of Health (F32HD105323)
- Carlos A Diaz-Balzac
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Lazaro-Pena et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons
eLife 12:e85792.
https://doi.org/10.7554/eLife.85792
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