HC fragment (C-terminal portion of the heavy chain) of tetanus toxin activates protein kinase C isoforms and phosphoproteins involved in signal transduction

Gil, Carles; Chaib-Oukadour, Imane; Blasi, Juan; Aguilera, José

doi:10.1042/0264-6021:3560097

Cited by 30 publications

(30 citation statements)

References 41 publications

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“…PKCδ is the member of the PKC family with the greatest number of described isoenzymes, generated by alternative splicing (from I to VIII), comprising either anti and proapoptotic isoforms [54]. In previous works from our group the induction of PKCδ translocation to membranes, an event related to its activation, was described by both TeTx [55] and Hc-TeTx [30], together with promotion of phospholipase Cγ-1 [30] and inositol phospholipid hydrolysis [56]. PKCδ has also been related to the formation of ceramide in the plasmatic membrane, since stimulated PKCδ is differentially trafficked to endolysosomes, causing phosphorylation and consequent targeting of acid SMase to the plasma membrane, where hydrolyzes SM to ceramide [57].…”

Section: Discussionmentioning

confidence: 99%

“…Another action exerted by Hc-TeTx in in vitro and in vivo models is the inhibition of apoptosis under stress situations or pathological conditions, thanks to the activation of signaling cascades involved in survival [30], [31]. Thus, Hc-TeTx prevents the death of granular neurons in culture due to potassium withdrawal [32] or due to acute treatment with 1-methyl-4-phenylpyridinium (MPP + ) [33].…”

Section: Introductionmentioning

confidence: 99%

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Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress

et al. 2013

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Tetanus toxin (TeTx) is the protein, synthesized by the anaerobic bacteria Clostridium tetani, which causes tetanus disease. TeTx gains entry into target cells by means of its interaction with lipid rafts, which are membrane domains enriched in sphingomyelin and cholesterol. However, the exact mechanism of host membrane binding remains to be fully established. In the present study we used the recombinant carboxyl terminal fragment from TeTx (Hc-TeTx), the domain responsible for target neuron binding, showing that Hc-TeTx induces a moderate but rapid and sustained increase in the ceramide/sphingomyelin ratio in primary cultures of cerebellar granule neurons and in NGF-differentiated PC12 cells, as well as induces the formation of ceramide platforms in the plasma membrane. The mentioned increase is due to the promotion of neutral sphingomyelinase activity and not to the de novo synthesis, since GW4869, a specific neutral sphingomyelinase inhibitor, prevents neutral sphingomyelinase activity increase and formation of ceramide platforms. Moreover, neutral sphingomyelinase inhibition with GW4869 prevents Hc-TeTx-triggered signaling (Akt phosphorylation), as well as the protective effect of Hc-TeTx on PC12 cells subjected to oxidative stress, while siRNA directed against nSM2 prevents protection by Hc-TeTx of NSC-34 cells against oxidative insult. Finally, neutral sphingomyelinase activity seems not to be related with the internalization of Hc-TeTx into PC12 cells. Thus, the presented data shed light on the mechanisms triggered by TeTx after membrane binding, which could be related with the events leading to the neuroprotective action exerted by the Hc-TeTx fragment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress

et al. 2013

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“…Several pathogens activate the MAP kinase pathway in order to gain entry into cells (Tang et al, 1998;Liu et al, 2002). TTC has been reported (Gil et al, 2000(Gil et al, , 2001(Gil et al, , 2003Chaïb-Oukadour et al, 2004) to activate intracellular pathways involving Trk receptors, and Gil et al (2003) have proposed that stimulation of Trk receptors by tetanus Values of b-gal activity retrogradely transported and thus detected under the ligature (B-segment only) represent the mean ± SD of three independent experiments. This activity was also expressed as percentage of internalized activity.…”

Section: Discussionmentioning

confidence: 99%

Brain‐derived neurotrophic factor facilitates in vivo internalization of tetanus neurotoxin C‐terminal fragment fusion proteins in mature mouse motor nerve terminals

Roux

Cloment

Curie

et al. 2006

Eur J of Neuroscience

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In a previous study it was reported that fusion proteins composed of the atoxic C-terminal fragment of tetanus toxin (TTC) and green fluorescent protein or beta-galactosidase (GFP-TTC and beta-gal-TTC, respectively) rapidly cluster at motor nerve terminals of the mouse neuromuscular junction (NMJ). Because this traffic involves presynaptic activity, probably via the secretion of active molecules, we examined whether it is affected by brain-derived neurotrophic factor (BDNF). Quantitative confocal microscopy and a fluorimetric assay for beta-gal activity revealed that co-injecting BDNF and the fusion proteins significantly increased the kinetics and amount of the proteins' localization at the NMJ and their internalization by motor nerve terminals. The observed increases were independent of synaptic vesicle recycling because BDNF did not affect spontaneous quantal acetylcholine release. In addition, injecting anti-BDNF antibody shortly before injecting GFP-TTC, and before co-injecting GFP-TTC and BDNF, significantly reduced the fusion protein's localization at the NMJ. Co-injecting GFP-TTC with neurotrophin-4 (NT-4) or glial-derived neurotrophic factor (GDNF), but not with nerve growth factor, neurotrophin-3 or ciliary neurotrophic factor, also significantly increased the fusion protein's localization at the NMJ. Thus, TTC probes may use for their neuronal internalization endocytic pathways normally stimulated by BDNF, NT-4 and GDNF binding. Different tyrosine kinase receptors with similar signalling pathways are activated by BDNF/NT-4 and GDNF binding. Thus, activated components of these signalling pathways may be involved in the TTC probes' internalization, perhaps by facilitating localization of receptors of TTC in specific membrane microdomains or by recruiting various factors needed for internalization of TTC.

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“…This signal pathway activation was dependent on time and concentration, suggesting that fragment C could exert neuroprotective effects, activating TrkA and TrkB receptors in a similar manner as do NGF and BDNF or neurotrophin-4/5 [85,86]. …”

Section: Possible Signaling Pathways For Fragment C Of Tetanus Toxinmentioning

confidence: 99%

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

Calvo

Oliván

Manzano

et al. 2012

IJMS

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When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C) can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP-2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport.

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HC fragment (C-terminal portion of the heavy chain) of tetanus toxin activates protein kinase C isoforms and phosphoproteins involved in signal transduction

Cited by 30 publications

References 41 publications

Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress

Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress

Brain‐derived neurotrophic factor facilitates in vivo internalization of tetanus neurotoxin C‐terminal fragment fusion proteins in mature mouse motor nerve terminals

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

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