Palmitoylation-dependent control of JAK1 kinase signaling governs responses to neuropoietic cytokines and survival in DRG neurons.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Cytokines*/metabolism ; Lipoylation* ; Neurons*/cytology ; Neurons*/metabolism ; Signal Transduction*; Animals ; Female ; Humans ; Mice ; Pregnancy ; Ganglia, Spinal/metabolism ; HEK293 Cells ; Janus Kinase 1/genetics ; Janus Kinase 1/metabolism ; Proteomics ; Cell Survival
    • Abstract:
      Janus Kinase-1 (JAK1) plays key roles during neurodevelopment and following neuronal injury, while activatory JAK1 mutations are linked to leukemia. In mice, Jak1 genetic deletion results in perinatal lethality, suggesting non-redundant roles and/or regulation of JAK1 for which other JAKs cannot compensate. Proteomic studies reveal that JAK1 is more likely palmitoylated compared to other JAKs, implicating palmitoylation as a possible JAK1-specific regulatory mechanism. However, the importance of palmitoylation for JAK1 signaling has not been addressed. Here, we report that JAK1 is palmitoylated in transfected HEK293T cells and endogenously in cultured Dorsal Root Ganglion (DRG) neurons. We further use comprehensive screening in transfected non-neuronal cells and shRNA-mediated knockdown in DRG neurons to identify the related enzymes ZDHHC3 and ZDHHC7 as dominant protein acyltransferases (PATs) for JAK1. Surprisingly, we found palmitoylation minimally affects JAK1 localization in neurons, but is critical for JAK1's kinase activity in cells and even in vitro. We propose this requirement is likely because palmitoylation facilitates transphosphorylation of key sites in JAK1's activation loop, a possibility consistent with structural models of JAK1. Importantly, we demonstrate a leukemia-associated JAK1 mutation overrides the palmitoylation-dependence of JAK1 activity, potentially explaining why this mutation is oncogenic. Finally, we show that JAK1 palmitoylation is important for neuropoietic cytokine-dependent signaling and neuronal survival and that combined Zdhhc3/7 loss phenocopies loss of palmitoyl-JAK1. These findings provide new insights into the control of JAK signaling in both physiological and pathological contexts.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Grant Information:
      R01 NS094402 United States NS NINDS NIH HHS; R35 GM122517 United States GM NIGMS NIH HHS; P30 CA006927 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Janus kinase (JAK); dorsal root ganglia; neuroscience; protein palmitoylation; signal transduction
    • Accession Number:
      0 (Cytokines)
      EC 2.7.10.2 (JAK1 protein, human)
      EC 2.7.10.2 (Janus Kinase 1)
    • Publication Date:
      Date Created: 20230625 Date Completed: 20230901 Latest Revision: 20240614
    • Publication Date:
      20240614
    • Accession Number:
      PMC10413081
    • Accession Number:
      10.1016/j.jbc.2023.104965
    • Accession Number:
      37356718