Slippery signaling: Palmitoylation-dependent control of neuronal kinase localization and activity

Montersino, Audrey; Thomas, Gareth M.

doi:10.1080/09687688.2016.1182652

Cited by 24 publications

(30 citation statements)

References 103 publications

(148 reference statements)

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“…This process requires specific localization of membrane proteins to axonal growth cones, where they act as markers for the delivery of new membrane and proteins via axonal transport (Barnes and Polleux, ). Several proteins implicated in neuronal polarization, including the small G proteins Rab10 and Cdc42 and the SAD protein kinases, are likely to be palmitoylated (Barnes et al, ; Blanc et al, ; Garvalov et al, ; Montersino and Thomas, ). These findings raise the possibility that polarization cues may induce palmitoylation‐dependent changes in the localization and/or turnover of these proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Palmitoyl‐DLK is thus unlikely to inappropriately phosphorylate cytosolic MAP2Ks, perhaps explaining how DLK can control retrograde signals without affecting physiological JNK signaling (Ghosh et al, ). Indeed, evidence from multiple other neuron types suggests that a key role for palmitoylation of neuronal kinases is to ensure their signaling specificity (Montersino and Thomas, ).…”

Section: Introductionmentioning

confidence: 99%

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Roles of palmitoylation in axon growth, degeneration and regeneration

Holland

Thomas

2017

J of Neuroscience Research

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The protein-lipid modification palmitoylation plays important roles in neurons, but most attention has focused on roles of this modification in the regulation of mature pre- and post-synapses. However, exciting recent findings suggest that palmitoylation is also critical for both the growth and integrity of neuronal axons and plays previously unappreciated roles in conveying axonal anterograde and retrograde signals. Here we review these emerging roles for palmitoylation in the regulation of axons in health and disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roles of palmitoylation in axon growth, degeneration and regeneration

Holland

Thomas

2017

J of Neuroscience Research

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“…Notably, most high-and medium-confidence validated proteins (75%) fall nicely into defined functional classes, indicating that PPT1 primarily influences related functions at the synapse. Literature suggests that palmitoylation regulates function of several of these protein classes, including ion channels and transporters, G-proteins, and mitochondrial proteins (Goddard and Watts, 2012;Montersino and Thomas, 2015;Shipston, 2011). Our findings that synaptic adhesion molecules, endocytic proteins and other lysosomal storage disease-linked proteins are regulated by depalmitoylation are novel.…”

Section: Classification Of Synaptic Substrates and Functionsmentioning

confidence: 57%

Identification of synaptic PPT1 substrates highlight roles of depalmitoylation in disulfide bond formation and synaptic function

Gorenberg

Tieze

Yücel

et al. 2020

Preprint

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Author contributions: ELG, HRZ, VC, and GSW conducted experiments. ELG and SSC designed experiments. ELG and JB performed data analysis. TTL conducted mass spectrometry. ELG and SSC wrote paper. All authors read and edited text. Highlights• 10% of palmitoylated proteins are palmitoyl protein thioesterase 1 (PPT1) substrates • Unbiased proteomic approaches identify 9 broad classes of substrates, including synaptic adhesion molecules and endocytic proteins • PPT1 depalmitoylates several transmembrane proteins in their extracellular domains • Depalmitoylation allows for disulfide bond formation in some PPT1 substrates • Protein degradation does not require depalmitoylation by PPT1 • Other palmitoylated Neuronal Ceroid Lipofuscinosis proteins are impacted by deficiency of PPT1, indicating a common disease pathway SUMMARYWe report here the identification of substrates of the depalmitoylating enzyme PPT1 by quantitative mass spectrometry. We first used a stringent Acyl Resin-Assisted Capture (Acyl RAC) screen in which PPT1 knockout (KO) mouse brain proteins showing increased in vivo palmitoylation are identified as putative PPT1 substrates. We then validated hits by directly depalmitoylating with PPT1 to confirm bona fide substrates. This novel twostep screen identified >100 substrates not previously known to be depalmitoylated by PPT1, including a wide range of channels/transporters, G-proteins, endo/exocytic components, synaptic adhesion molecules, and mitochondrial proteins. Interestingly, many sites of depalmitoylation on transmembrane proteins were located in extracellular domains facing the synaptic cleft. For this group of substrates, depalmitoylation appears to facilitate disulfide bond formation. Collectively, these diverse substrates may explain the many facets of CLN1 disease caused by the loss of PPT1 function.

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“…Palmitoylation can effectively act as a post-translational "switch" on some proteins and provide dynamic control over protein localization or function. Indeed, palmitoylation plays critical roles in protein trafficking and strongly influences the stability of proteins [64][65][66][67][68][69]. PPT1 is a lysosomal substrate that enter in the lysosome via autophagy leading to signaling of several processes related with anabolic and catabolic metabolism in the cell [63,70].…”

Section: Discussionmentioning

confidence: 99%

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

Álvarez-Izquierdo

Esteban

Muñoz-Antolí

et al. 2020

Preprint

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Abstract Background: Echinostoma caproni (Trematoda: Echinostomatidae) is an intestinal trematode, which has been widely employed to investigate the factors determining the rejection of intestinal helminths. In this sense, several studies have shown that IL-25 is essential for the development of resistance against E. caproni in mice. In fact, treatment of mice with recombinant IL-25 generates resistance against primary E. caproni infection. However, the mechanisms by which IL-25 induces resistance remain unknown.Methods: To study the mechanisms responsible for resistance elicited by IL-25, we analyze the ileal proteomic changes induced by IL-25 in mice and their potential role in resistance. To this purpose, we compare the protein expression profiles in the ileum of four experimental groups of mice: naïve controls; E. caproni-infected mice; rIL-25-treated mice; and rIL-25-treated mice exposed to E. caproni metacercariae.Results: Quantitative comparison by 2D-DIGE showed significant changes in a total of 41 spots. Forty of those spots validated protein spots were were identified by mass spectrometry corresponding to 24 proteins.Conclusions: The analysis of differentially expressed proteins indicates that maintenance of the intestinal epithelial homeostasis and the regulation of proliferation and cell death are the most affected processes that appears to be related to the resistance to infection. These results provide new insights into the proteins involved in the regulation of tissue homeostasis after intestinal infection and its transcendence in resistance.

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Slippery signaling: Palmitoylation-dependent control of neuronal kinase localization and activity

Cited by 24 publications

References 103 publications

Roles of palmitoylation in axon growth, degeneration and regeneration

Roles of palmitoylation in axon growth, degeneration and regeneration

Identification of synaptic PPT1 substrates highlight roles of depalmitoylation in disulfide bond formation and synaptic function

Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections

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