JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis
Open accessAbstract
Neurons are highly polarized cells that often project axons a considerable distance. To respond to axonal damage, neurons must transmit a retrograde signal to the nucleus to enable a transcriptional stress response. Here we describe a mechanism by which this signal is propagated through injury-induced stabilization of dual leucine zipper-bearing kinase (DLK/MAP3K12). After neuronal insult, specific sites throughout the length of DLK underwent phosphorylation by c-Jun N-terminal kinases (JNKs), which have been shown to be downstream targets of DLK pathway activity. These phosphorylation events resulted in increased DLK abundance via reduction of DLK ubiquitination, which was mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme USP9X. Abundance of DLK in turn controlled the levels of downstream JNK signaling and apoptosis. Through this feedback mechanism, the ubiquitin–proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults.
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At baseline, NLK is highly expressed in the CNS, and its expression is unregulated by oxidative and osmotic stress.
“At baseline, NLK is highly expressed in the CNS, and its expression is unregulated by oxidative and osmotic stress (52, 53), conditions associated with the cytosolic accumulation of TDP43 and other, predominantly nuclear, RNA binding proteins.”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [53]
The Results section on neuronal stress examines DLK levels after nerve growth factor withdrawal, not NLK expression. Searches for NLK, CNS baseline expression, and oxidative or osmotic stress found no passage addressing the attributed claim. Page numbers are unavailable in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredA pathway involving DLK, JNK, and PERK has previously been implicated in neuronal death.
“A pathway involving DLK, JNK and PERK has previously been implicated in neuronal death (Ghosh et al., 2011; Huntwork-Rodriguez et al., 2013; Larhammar et al., 2017; Miller et al., 2009; Pozniak et al., 2013; Watkins et al., 2013; Welsbie et al., 2013), validating our approach.”
From CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons (2019) · cites this paper as Huntwork-Rodriguez et al., 2013
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References 62 · Cited by 154
- Authors
- Huntwork-Rodriguez, S., Wang, B., Watkins, T., Ghosh, A. S., Pozniak, C. D., Bustos, D., Newton, K., Kirkpatrick, D. S., & Lewcock, J. W.
- Affiliations
- Department of Neuroscience 1 , 2 , and 3
- Genentech (US)
- Corresponding author
- Lewcock, Joseph W.
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2013-08-26
- Volume
- 202
- Issue
- 5
- Pages
- 747-763
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3760612
- OpenAlex
- W2133711843
- Cited by
- 154
- References
- 62
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 21 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 13 · 2017: 16 · 2016: 19 · 2015: 13 · 2014: 12 · 2013: 4
- FWCI
- 7.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- DLK, MAP3K12, JNK phosphorylation, ubiquitination, neuronal apoptosis, retrograde signaling, axonal injury, PHR1, USP9X, ubiquitin-proteasome system, protein stability, stress response
- MeSH terms
- Animals, Axons, Embryo, Mammalian, Enzyme Activation, Enzyme Stability, Humans, Models, Biological, Molecular Weight, Nerve Crush, Optic Nerve, Phosphorylation, Sensory Receptor Cells, Stress, Physiological, Signal Transduction, Apoptosis, MAP Kinase Kinase Kinases, Nerve Growth Factor, Ubiquitin, Proteasome Endopeptidase Complex, JNK Mitogen-Activated Protein Kinases, Mice, Ubiquitination, HEK293 Cells
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