Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/85792 |
| _version_ | 1797767088122626048 |
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| author | Maria I Lazaro-Pena Adam B Cornwell Carlos A Diaz-Balzac Ritika Das Zachary C Ward Nicholas Macoretta Juilee Thakar Andrew V Samuelson |
| author_facet | Maria I Lazaro-Pena Adam B Cornwell Carlos A Diaz-Balzac Ritika Das Zachary C Ward Nicholas Macoretta Juilee Thakar Andrew V Samuelson |
| author_sort | Maria I Lazaro-Pena |
| collection | DOAJ |
| description | 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 that 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 γ-aminobutyric acid (GABA)ergic 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. |
| first_indexed | 2024-03-12T20:34:36Z |
| format | Article |
| id | doaj.art-c298475de3254457ae6029f66836d12b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T20:34:36Z |
| publishDate | 2023-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c298475de3254457ae6029f66836d12b2023-08-01T15:46:36ZengeLife Sciences Publications LtdeLife2050-084X2023-06-011210.7554/eLife.85792Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neuronsMaria I Lazaro-Pena0https://orcid.org/0000-0002-3061-8835Adam B Cornwell1https://orcid.org/0000-0002-0572-3107Carlos A Diaz-Balzac2https://orcid.org/0000-0002-4723-1282Ritika Das3Zachary C Ward4Nicholas Macoretta5Juilee Thakar6Andrew V Samuelson7https://orcid.org/0000-0002-3071-5766Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United StatesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, United StatesDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, United StatesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States; Department of Biology, University of Rochester, Rochester, United States; Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, United StatesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, United StatesDepartment of Biology, University of Rochester, Rochester, United StatesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States; Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, United States; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, United StatesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, United StatesAging 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 that 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 γ-aminobutyric acid (GABA)ergic 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.https://elifesciences.org/articles/85792proteostasislongevityneuronal cell non-autonomous controlaginggene expressionhomeodomain-interacting protein kinase |
| spellingShingle | Maria I Lazaro-Pena Adam B Cornwell Carlos A Diaz-Balzac Ritika Das Zachary C Ward Nicholas Macoretta Juilee Thakar Andrew V Samuelson Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons eLife proteostasis longevity neuronal cell non-autonomous control aging gene expression homeodomain-interacting protein kinase |
| title | Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| title_full | Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| title_fullStr | Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| title_full_unstemmed | Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| title_short | Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons |
| title_sort | homeodomain interacting protein kinase maintains neuronal homeostasis during normal caenorhabditis elegans aging and systemically regulates longevity from serotonergic and gabaergic neurons |
| topic | proteostasis longevity neuronal cell non-autonomous control aging gene expression homeodomain-interacting protein kinase |
| url | https://elifesciences.org/articles/85792 |
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