Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

Zhong, Zhisheng; Grasso, Laura; Sibilla, Caroline; Stevens, Tim J.; Barry, Nicolas P. E.; Bertolotti, Anne

doi:10.15252/embj.201797822

Cited by 27 publications

(21 citation statements)

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“…For example, Fascin is a critical component downstream of Rac1 that is needed for actin cytoskeletal organization and cell motility . RhoA regulates phosphorylation of cofilin‐1 and activity of annexin A2, thereby regulating cytoskeletal organization and cell adhesion .Therefore, we wondered if RhoA and Rac1 were added to the network analysis. Interestingly, these proteins were linked together and an integrated network was shown when RhoA and Rac1 were added to the analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

et al. 2019

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Voltage‐gated sodium channels are involved in tumor metastasis, as potentiating or attenuating their activities affects the migration and invasion process of tumor cells. In the present study, we tested the effect of two peptide toxins, JZTX‐I and HNTX‐III which function as Nav1.7 activator and inhibitor, respectively, on the migration and invasion ability of prostate cancer (PCa) cell line Mat‐LyLu. These two peptides showed opposite effects, and subsequently a comparative proteomic analysis characterized 64 differentially expressed membrane proteins from the JZTX‐I‐ and HNTX‐III‐treated groups. Among these, 15 proteins were down‐regulated and 49 proteins were up‐regulated in the HNTX‐III group. Bioinformatic analysis showed eight proteins are cytoskeleton proteins or related regulators, which might play important roles in the metastasis of Mat‐LyLu cells. The altered expressions of four of these proteins, fascin, muskelin, annexin A2, and cofilin‐1, were validated by western blot analysis. Further function network analysis of these proteins revealed that the Rho family GTPases RhoA and Rac1 might be of particular importance for the rat PCa cell invasion. Pharmacological data revealed that JZTX‐I and HNTX‐III could modulate the Rho signaling pathway in a Nav1.7‐dependent manner. In summary, this study suggests that the Nav1.7‐dependent regulation of Rho GTPase activity plays a vital role in Mat‐LyLu cell migration and invasion and provides new insights into the treatment of PCa.

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Section: Resultsmentioning

confidence: 99%

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

et al. 2019

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“…A previous study by our group demonstrated that silencing of cofilin inhibits PMA- and growth factor-induced membrane ruffling and macropinocytosis in macrophages (10). Recently, Zhong et al, using pharmacological and genetic approaches have shown an important role for cofilin and actin polymerization in macropinocytic entry of prion-like protein aggregates in neuroblasts (63). The results of the present study demonstrated that PMA and HGF treatments dephosphorylate cofilin at Ser-3 in wild-type macrophages and activation of cofilin is significantly attenuated in PKCδ knockout macrophages.…”

Section: Discussionmentioning

confidence: 99%

PKCδ stimulates macropinocytosis via activation of SSH1-cofilin pathway

Singla

Lin

Ghoshal

et al. 2019

Cellular Signalling

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Macropinocytosis is an actin-dependent endocytic mechanism mediating internalization of extracellular fluid and associated solutes into cells. The present study was designed to identify the specific protein kinase C (PKC) isoform(s) and downstream effectors regulating actin dynamics during macropinocytosis. We utilized various cellular and molecular biology techniques, pharmacological inhibitors and genetically modified mice to study the signaling mechanisms mediating macropinocytosis in macrophages. The qRT-PCR experiments identified PKCδ as the predominant PKC isoform in macrophages. Scanning electron microscopy and flow cytometry analysis of FITC-dextran internalization demonstrated the functional role of PKCδ in phorbol ester- and hepatocyte growth factor (HGF)-induced macropinocytosis. Western blot analysis demonstrated that phorbol ester and HGF stimulate activation of slingshot phosphatase homologue 1 (SSH1) and induce cofilin Ser-3 dephosphorylation via PKCδ in macrophages. Silencing of SSH1 inhibited cofilin dephosphorylation and macropinocytosis stimulation. Interestingly, we also found that incubation of macrophages with BMS-5, a potent inhibitor of LIM kinase, does not stimulate macropinocytosis. In conclusion, the findings of the present study demonstrate a previously unidentified mechanism by which PKCδ via activation of SSH1 and cofilin dephosphorylation stimulates membrane ruffle formation and macropinocytosis. The results of the present study may contribute to a better understanding of the regulatory mechanisms during macrophage macropinocytosis.

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“…It is currently unclear what the major mechanism of synaptic tau secretion is, but the evidence so far suggests: (1) release from synaptic vesicles [242] (2) secretion in extracellular vesicles such as exosomes [241, 256, 313] and ectosomes [80], (3) direct translocation across the membrane [157, 208] or (4) tunneling nanotubes [1, 295]. Similarly, several tau uptake mechanisms have been identified which are not mutually exclusive: (1) bulk endocytosis [98, 121, 259, 317] macropinocytosis by heparin sulfate proteoglycans [84, 132, 162, 248, 288, 328] or (3) clathrin-mediated endocytosis [49, 82]. After tau seeds enter the neuron they can seed physiological monomers, thereby propagating the disease process [85].…”

Section: Introductionmentioning

confidence: 99%

Intersection of pathological tau and microglia at the synapse

Vogels

Murgoci

Hromádka

2019

acta neuropathol commun

146

141

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Tauopathies are a heterogenous class of diseases characterized by cellular accumulation of aggregated tau and include diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy and chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration and clinical symptoms in tauopathy patients. Furthermore, synapse loss is an early pathological event in tauopathies and is the strongest correlate of cognitive decline. Tau pathology is additionally associated with chronic neuroinflammatory processes, such as reactive microglia, astrocytes, and increased levels of pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that as the principal immune cells of the brain, microglia play a particularly important role in the initiation and progression of tau pathology and associated neurodegeneration. Furthermore, AD risk genes such as Triggering receptor expressed on myeloid cells 2 ( TREM2 ) and Apolipoprotein E ( APOE ) are enriched in the innate immune system and modulate the neuroinflammatory response of microglia to tau pathology. Microglia can play an active role in synaptic dysfunction by abnormally phagocytosing synaptic compartments of neurons with tau pathology. Furthermore, microglia are involved in synaptic spreading of tau – a process which is thought to underlie the progressive nature of tau pathology propagation through the brain. Spreading of pathological tau is also the predominant target for tau-based immunotherapy. Active tau vaccines, therapeutic tau antibodies and other approaches targeting the immune system are actively explored as treatment options for AD and other tauopathies. This review describes the role of microglia in the pathobiology of tauopathies and the mechanism of action of potential therapeutics targeting the immune system in tauopathies.

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Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

Cited by 27 publications

References 50 publications

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

PKCδ stimulates macropinocytosis via activation of SSH1-cofilin pathway

Intersection of pathological tau and microglia at the synapse

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