TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching

Plooster, Melissa; Menon, Shalini; Winkle, Cortney C.; Urbina, Fabio; Monkiewicz, Caroline; Phend, Kristen D.; Weinberg, Richard J.; Gupton, Stephanie L.

doi:10.1091/mbc.e16-08-0594

Cited by 45 publications

(77 citation statements)

References 58 publications

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“…This indicated the ligase domain was unnecessary to constrain exocytosis, but required for response to netrin. Although previous studies identified TRIM9-dependent ubiquitination of substrates as a mechanism to alter substrate function (Menon et al, 2015;Plooster et al, 2017), we did not observe netrin-1 or TRIM9-dependent changes in the ubiquitination of SNAP25 ( Figure S4C), suggesting that ubiquitin-dependent modulation of SNAP25 did not explain TRIM9-dependent changes in exocytosis. Expression of TRIM9ΔSPRY or TRIM9ΔCC failed to reduce the elevated frequency of exocytosis in the neurites (P = 0.23 and P = 0.33, respectively, Figure 5C) or the netrin-dependent reduction in temporal clustering ( Figure S4B).…”

Section: Different Domains Of Trim9 Modulate Specific Parameters Of Econtrasting

confidence: 93%

“…A potential range of vesicular surface areas was approximated from vesicle diameters measured from transmission electron microscopy (TEM) images of cortical neurons at 48 hours in vitro, with the assumption that vesicles were spherical ( Figure 3A). To correct for capturing random slices through vesicles, we took the conservative estimate that the 25th percent of the interquartile range represented the diameter of the smallest vesicles (80 nm) and the 75th percent of the interquartile-range represented the diameter of largest vesicles (130 nm, Plooster and Menon et al, 2017). We estimated membrane addition between 24 and 48 hours in vitro, using the formula where y represents the predicted neuronal surface area at 48 hours, S is the neuronal surface area at 24 hours, f24 and f48 are the exocytic frequency at 24 and 48 hours, respectively, and z is the surface area of vesicles.…”

Section: A Mathematical Approximation Of Membrane Expansion In Develomentioning

confidence: 99%

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Dynamic Spatiotemporal Organization of Exocytosis During Cellular Shape Change

Urbina

Gómez

Gupton

2017

Preprint

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Morphological elongation of developing neurons requires plasmalemma expansion, hypothesized to occur primarily via exocytosis. We posited that exocytosis in developing neurons and non-neuronal cells exhibit distinct spatiotemporal organization. We exploited TIRF microscopy to image VAMP-pHluorin mediated exocytosis in murine embryonic cortical neurons and interphase melanoma cells, and developed computer-vision software and statistical tools to uncover spatiotemporal aspects of exocytosis. Vesicle fusion behavior differed between vesicle types, cell types, developmental stage, and extracellular environment. Experiment-based mathematical calculations indicated that VAMP2-mediated vesicle fusion supplied excess material for the plasma membrane expansion that occurred early in neuronal morphogenesis, which was balanced in part by clathrin-mediated endocytosis. Spatial statistics uncovered distinct spatiotemporal regulation of exocytosis in the soma and neurites of developing neurons that was modulated by developmental stage, exposure to the guidance cue netrin-1, and the brain-enriched ubiquitin ligase TRIM9. In melanoma cells, exocytosis occurred less frequently with distinct spatial clustering patterns.

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Section: Different Domains Of Trim9 Modulate Specific Parameters Of Econtrasting

confidence: 93%

Section: A Mathematical Approximation Of Membrane Expansion In Develomentioning

confidence: 99%

Dynamic Spatiotemporal Organization of Exocytosis During Cellular Shape Change

Urbina

Gómez

Gupton

2017

Preprint

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“…TRIM9 also interacts with and ubiquitinates DCC, a transmembrane receptor for netrin-1 [5,17], and the actin polymerase VASP [8]. Upon binding of netrin-1 to its receptor DCC, TRIM9 releases SNAP25 and VASP is deubiquitinated, promoting vesicle fusion, membrane expansion, and membrane protrusion [5,8].…”

Section: Discussionmentioning

confidence: 99%

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

Gupton

Tanji

et al. 2018

Cerebellum

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Objective: To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Methods: Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67 and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. Results: We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Interpretation: Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

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“…For example, Ena/vasodilator stimulated phosphoprotein (VASP) actin polymerases are critical to filopodia formation and maintenance in neurons (Dent et al, 2007; Kwiatkowski et al, 2007), particularly downstream of DCC and netrin-1 (Lebrand et al, 2004). Recent work demonstrated that negative regulation of downstream effectors primes the neuron for appropriate netrin response (Menon et al, 2015; Plooster et al, 2017). For example, E3 ubiquitin ligase tripartite motif protein 9 (TRIM9) is required for ubiquitination and inhibition of the actin polymerase VASP (Menon et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance

Boyer

McCormick

Menon

et al. 2019

Journal of Cell Biology

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Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered sensors for axon guidance cues, yet how they respond to extracellular cues remains ill defined. Our previous work found that the filopodial actin polymerase VASP and consequently filopodial stability are negatively regulated via nondegradative TRIM9-dependent ubiquitination. Appropriate VASP ubiquitination and deubiquitination are required for axon turning in response to the guidance cue netrin-1. Here we show that the TRIM9-related protein TRIM67 outcompetes TRIM9 for interacting with VASP and antagonizes TRIM9-dependent VASP ubiquitination. The surprising antagonistic roles of two closely related E3 ubiquitin ligases are required for netrin-1–dependent filopodial responses, axon turning and branching, and fiber tract formation. We suggest a novel model in which coordinated regulation of VASP ubiquitination by a pair of interfering ligases is a critical element of VASP dynamics, filopodial stability, and axon guidance.

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TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching

Cited by 45 publications

References 58 publications

Dynamic Spatiotemporal Organization of Exocytosis During Cellular Shape Change

Dynamic Spatiotemporal Organization of Exocytosis During Cellular Shape Change

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance

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