The Highwire Ubiquitin Ligase Promotes Axonal Degeneration by Tuning Levels of Nmnat Protein

Highwire, a conserved axonal E3 ubiquitin ligase, regulates the initiation of axonal degeneration after injury in Drosophila by regulating the levels of the NAD+ biosynthetic enzyme, Nmnat, and the Wnd kinase.

• Publication year

  2012

• Venue

  PLoS Biology

• Publication date

  2012-12-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pbio.1001440PMID 23226106PMCID 3514318
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway

  2012cited by this paper
• NMNAT suppresses tau-induced neurodegeneration by promoting clearance of hyperphosphorylated tau oligomers in a Drosophila model of tauopathy.

  2012cited by this paper
• CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy.

  2012cited by this paper
• Axon degeneration and regeneration: insights from Drosophila models of nerve injury.

  2012cited by this paper
• S ration through Increased Mitochondrial Flux and Enhanced Mitochondrial Ca 2 + Buffering

  2012influential reference
• Axon degeneration: Molecular mechanisms of a self-destruction pathway

  2012cited by this paper
• A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity.

  2012cited by this paper
• Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration.

  2012cited by this paper
• A Conditioning Lesion Protects Axons from Degeneration via the Wallenda/DLK MAP Kinase Signaling Cascade

  2012cited by this paper
• ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation

  2011cited by this paper
• Nmnat exerts neuroprotective effects in dendrites and axons.

  2011cited by this paper
• Drosophila homeodomain-interacting protein kinase inhibits the Skp1-Cul1-F-box E3 ligase complex to dually promote Wingless and Hedgehog signaling

  2011cited by this paper
• Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons

  2010influential reference
• Wallerian degeneration, wld(s), and nmnat.

  2010influential reference
• PHRs: bridging axon guidance, outgrowth and synapse development.

  2010cited by this paper
• Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury

  2010cited by this paper
• Expression, Localization, and Biochemical Characterization of Nicotinamide Mononucleotide Adenylyltransferase 2*

  2010cited by this paper
• Wallerian degeneration of zebrafish trigeminal axons in the skin is required for regeneration and developmental pruning

  2010cited by this paper
• Overexpression of Wlds or Nmnat2 in mauthner cells by single‐cell electroporation delays axon degeneration in live zebrafish

  2010cited by this paper
• Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration

  2009cited by this paper
• A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration

  2009cited by this paper
• WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration

  2009influential reference
• Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development

  2009cited by this paper
• Principles of ubiquitin and SUMO modifications in DNA repair

  2009cited by this paper
• Axon Regeneration Requires a Conserved MAP Kinase Pathway

  2009cited by this paper
• Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton

  2009cited by this paper
• PHR Regulates Growth Cone Pausing at Intermediate Targets through Microtubule Disassembly

  2009cited by this paper
• Impaired regenerative response of primary sensory neurons in ZPK/DLK gene-trap mice.

  2009cited by this paper
• The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration.

  2009cited by this paper
• Cellular and molecular determinants targeting the Caenorhabditis elegans PHR protein RPM‐1 to perisynaptic regions

  2008cited by this paper
• Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling.

  2008cited by this paper
• NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

  2008cited by this paper
• The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons.

  2007cited by this paper
• The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics.

  2007cited by this paper
• A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila

  2007cited by this paper
• HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

  2007cited by this paper
• The Deubiquitinating Enzyme Ubp2 Modulates Rsp5-dependent Lys63-linked Polyubiquitin Conjugates in Saccharomyces cerevisiae*>

  2006cited by this paper
• The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons.

  2006influential reference
• Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning.

  2006cited by this paper
• Highwire restrains synaptic growth by attenuating a MAP kinase signal.

  2006cited by this paper
• Drosophila NMNAT Maintains Neural Integrity Independent of Its NAD Synthesis Activity

  2006influential reference
• Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms*

  2005cited by this paper
• Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc)

  2005cited by this paper
• Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development.

  2005influential reference
• The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme

  2005cited by this paper
• Highwire Function at the Drosophila Neuromuscular Junction: Spatial, Structural, and Temporal Requirements

  2005cited by this paper
• Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling.

  2005cited by this paper
• Increased Expression of the Drosophila Vesicular Glutamate Transporter Leads to Excess Glutamate Release and a Compensatory Decrease in Quantal Content

  2004cited by this paper
• RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis

  2004cited by this paper
• Evidence for a Conserved Function in Synapse Formation Reveals Phr1 as a Candidate Gene for Respiratory Failure in Newborn Mice

  2004cited by this paper
• Differential Localization of Glutamate Receptor Subunits at the Drosophila Neuromuscular Junction

  2004cited by this paper
• Highwire regulates presynaptic BMP signaling essential for synaptic growth.

  2004influential reference
• An SCF-like ubiquitin ligase complex that controls presynaptic differentiation

  2004cited by this paper
• Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration.

  2003cited by this paper
• The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy.

  2003cited by this paper
• Structural Characterization of a Human Cytosolic NMN/NaMN Adenylyltransferase and Implication in Human NAD Biosynthesis* 210

  2003cited by this paper
• Creation of a GAL4/UAS‐coupled inducible gene expression system for use in drosophila cultured cell lines

  2002cited by this paper
• Targeted expression of dominant negative proteasome mutants in drosophila melanogaster

  2002influential reference
• Vectors for the expression of tagged proteins in Drosophila.

  2001cited by this paper
• Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene

  2001cited by this paper
• Ubiquitination-dependent mechanisms regulate synaptic growth and function

  2001influential reference
• Ubiquitin Is Required for Sorting to the Vacuole of the Yeast General Amino Acid Permease, Gap1*

  2001cited by this paper
• Highwire regulates synaptic growth in Drosophila.

  2000influential reference
• An olfactory sensory map in the fly brain.

  2000cited by this paper
• Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain.

  2000cited by this paper
• rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans.

  2000cited by this paper
• Postsynaptic filopodia in muscle cells interact with innervating motoneuron axons

  2000cited by this paper
• Ubiquitin Lys63 is involved in ubiquitination of a yeast plasma membrane protein

  1997cited by this paper
• Modulatory action of epidermal growth factor on differentiated human granulosa lutein cells: cross-talk between ligand activated receptors for EGF and gonadotropin.

  1996influential reference
• Improved stability of Drosophila larval neuromuscular preparations in haemolymph-like physiological solutions

  1994cited by this paper
• Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP2 and UBP3, and functional analysis of the UBP gene family.

  1992influential reference
• Consequences of slow Wallerian degeneration for regenerating motor and sensory axons.

  1992cited by this paper
• Delayed wallerian degeneration in sciatic nerves of C57BL/Ola mice is associated with impaired regeneration of sensory axons.

  1990cited by this paper
• Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve

  1989cited by this paper
• National Institute of Environmental Health Sciences third science seminar. Research Triangle Park, North Carolina, November 1982. Science open house poster sessions: Abstracts.

  1983cited by this paper
• Experiments on the Section of the Glosso-Pharyngeal and Hypoglossal Nerves of the Frog, and Observations of the Alterations Produced Thereby in the Structure of Their Primitive Fibres

  1851cited by this paper

• Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration.

  2026cites this paper
• Programmed axon degeneration: mechanism, inhibition and therapeutic potential

  2025cites this paper
• Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces

  2025cites this paper
• Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

  2025cites this paper
• Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic

  2025cites this paper
• Axonal injury signaling is restrained by a spared synaptic branch

  2025cites this paper
• A dNmnat-sensitized in vivo platform for unbiased discovery of regulators of neurodegeneration

  2025cites this paper
• SCFFBXO21-mediated ubiquitination and degradation of NMNAT2 regulates axon survival in nerve injury.

  2025cites this paper
• The Roles of Moonlighting Nicotinamide Mononucleotide Adenylyl Transferases in Cell Physiology

  2025cites this paper
• Increased ATP production and P‐glycoprotein activity underlie the marked changes in blood–brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis

  2025cites this paper
• Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

  2025cites this paper
• Peripheral Nerve Crush in Drosophila Larvae.

  2024cites this paper
• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

  2024cites this paper
• Local translatome sustains synaptic function in impaired Wallerian degeneration

  2024cites this paper
• Rab11 suppresses neuronal stress signaling by localizing dual leucine zipper kinase to axon terminals for protein turnover

  2024cites this paper
• Autophagy, the Ubiquitin proteasome system, and the MAPK pathway control the temperature dependence of synaptic growth

  2024cites this paper
• Ubiquitin ligase signalling networks shape presynaptic development, function and disease

  2024influential citation
• Molecular regulation of axon termination in mechanosensory neurons.

  2024cites this paper
• The role of the ubiquitin system in the onset and reversal of neuropathic pain.

  2024cites this paper
• Opposing roles of Fos, Raw, and SARM1 in the regulation of axonal degeneration and synaptic structure

  2023cites this paper
• Title: The axonal localization of Dual Leucine Zipper Kinase defines its protein-turnover

  2023cites this paper
• SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities

  2023cites this paper
• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase 2 receptor function 3

  2023cites this paper
• Tau-mediated axonal degeneration is prevented by activation of the WldS pathway

  2023cites this paper
• Phagocytosis drives NAD + reduction-induced dendrite degeneration in Drosophila

  2023cites this paper
• The Molecular Mechanisms Involved in Axonal Degeneration and Retrograde Retinal Ganglion Cell Death

  2023influential citation
• Deubiquitination of SARM1 by USP13 regulates SARM1 activation and axon degeneration

  2023cites this paper
• A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration

  2023influential citation
• NAD+, Axonal Maintenance, and Neurological Disease

  2023cites this paper
• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

  2023cites this paper
• Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration

  2022cites this paper
• The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila

  2022influential citation
• The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma

  2022cites this paper
• Non-lysine ubiquitylation: Doing things differently

  2022cites this paper
• Multifaceted roles of SARM1 in axon degeneration and signaling

  2022cites this paper
• A new dawn beyond lysine ubiquitination

  2022cites this paper
• Distinct developmental and degenerative functions of SARM1 require NAD+ hydrolase activity

  2022cites this paper
• Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

  2022influential citation
• An atypical ubiquitin ligase at the heart of neural development and programmed axon degeneration

  2022cites this paper
• Insights into nervous system repair from the fruit fly

  2022influential citation
• SARM1 can be a potential therapeutic target for spinal cord injury

  2022cites this paper
• Involvement of HECT-type E3 ubiquitin ligase genes in salt chemotaxis learning in C. elegans.

  2022cites this paper
• NMNAT2 Is Downregulated in Glaucomatous RGCs and RGC-Specific Gene Therapy Rescues Neurodegeneration and Visual Function.

  2022cites this paper
• Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.

  2021cites this paper
• Synaptic homeostats: latent plasticity revealed at the Drosophila neuromuscular junction

  2021cites this paper
• The Drama of Wallerian Degeneration: The Cast, Crew, and Script.

  2021cites this paper
• Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed.

  2021cites this paper
• The key role of the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase in regulating cell functions

  2021cites this paper
• Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

  2021cites this paper
• Linking Neuronal Protein Phosphatase 2A to the DLK Stress Kinase Signaling Cascade

  2021cites this paper
• Historical perspective and progress on protein ubiquitination at glutamatergic synapses.

  2021cites this paper
• A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity

  2021cites this paper
• The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin

  2021cites this paper
• Sleep Regulates Glial Plasticity and Expression of the Engulfment Receptor Draper Following Neural Injury.

  2020cites this paper
• TIR-1/SARM1 Inhibits Axon Regeneration

  2020cites this paper
• Cell death in animal development

  2020cites this paper
• Programmed axon degeneration: from mouse to mechanism to medicine

  2020cites this paper
• Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster

  2020cites this paper
• Sleep: The Balm of Hurt Minds.

  2020cites this paper
• Morphological and Functional Evaluation of Axons and their Synapses during Axon Death in Drosophila melanogaster.

  2020cites this paper
• Phagocytosis and self-destruction execute dendrite degeneration of Drosophila sensory neurons at distinct levels of NAD+ reduction

  2020cites this paper
• Targeting the Programmed Axon Degeneration Pathway as a Potential Therapeutic for Charcot-Marie-Tooth Disease.

  2020cites this paper
• Bidirectional Regulation of Sleep and Synapse Pruning after Neural Injury.

  2020cites this paper
• Tau-mediated axonal degeneration is prevented by activation of the WldS pathway

  2020influential citation
• Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.

  2020cites this paper
• Structural and Functional Plasticity in the Regenerating Olfactory System of the Migratory Locust

  2020cites this paper
• In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration

  2020cites this paper
• The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease.

  2020cites this paper
• The Enzymatic Function of the TIR domain: From Axon Degeneration to Innate Immunity

  2020cites this paper
• Structural basis for RING-Cys-Relay E3 Ligase Activity and its Role in Axon Integrity

  2020cites this paper
• Progress in Neurobiology

  2019cites this paper
• FBXO 45-MYCBP 2 regulates mitotic cell fate by targeting FBXW 7 for 2 degradation 3 4

  2019cites this paper
• Axonal fusion: An alternative and efficient mechanism of nerve repair

  2019cites this paper
• The E3 ligase Highwire promotes synaptic transmission by targeting the NAD‐synthesizing enzyme dNmnat

  2019influential citation
• Axon degeneration: mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy

  2019influential citation
• Mechanisms of injury-induced axon degeneration.

  2019cites this paper
• Die in pieces: How Drosophila sheds light on neurite degeneration and clearance.

  2019influential citation
• Axon injury signaling and compartmentalized injury response in glaucoma.

  2019cites this paper
• Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

  2019cites this paper
• Axon death signalling in Wallerian degeneration among species and in disease

  2019cites this paper
• Sarm1 deletion reduces axon damage, demyelination, and white matter atrophy after experimental traumatic brain injury.

  2019cites this paper
• Sleep regulates the glial engulfment receptor Draper to promote Wallerian degeneration

  2019cites this paper
• Cell Death and Neurodegeneration.

  2019cites this paper
• Degeneration of Injured Axons and Dendrites Requires Restraint of a Protective JNK Signaling Pathway by the Transmembrane Protein Raw

  2019influential citation
• Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44

  2019cites this paper
• Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss

  2019cites this paper
• Autophagy is inhibited by ubiquitin ligase activity in the nervous system

  2019cites this paper
• Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex

  2018cites this paper
• FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation

  2018cites this paper
• Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity

  2018cites this paper
• Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration

  2018influential citation
• PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

  2018influential citation
• Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis

  2018cites this paper
• An axonal stress response pathway: degenerative and regenerative signaling by DLK.

  2018cites this paper
• Palmitoylation enables MAPK-dependent proteostasis of axon survival factors

  2018cites this paper
• Maintenance mechanisms of circuit-integrated axons.

  2018cites this paper
• Therapeutic opportunities and pitfalls in the treatment of axon degeneration

  2018cites this paper
• Pebbled makes ripples: A transcription factor primes glutamatergic but not cholinergic neurons for degeneration

  2018cites this paper
• Distinct homeostatic modulations stabilize reduced postsynaptic receptivity in response to presynaptic DLK signaling

  2018cites this paper
• BMP signaling downstream of the Highwire E3 ligase sensitizes nociceptors

  2018cites this paper