CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-34. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. As no differences were detected on monocyte differentiation, we investigated the effect of CSF-1 and IL-34 on macrophage polarization into the M1 or M2 phenotype. We highlighted a striking increase in IL-10 and CCL17 secretion in M1 and M2 macrophages derived from IL-34 stimulated monocytes, respectively, compared to CSF-1 stimulated monocytes. Variations in the secretome induced by CSF-1 or IL-34 may account for their different ability to polarize naïve T cells into Th1 cells. In conclusion, our findings indicate that CSF-1 and IL-34 exhibit the same ability to induce human monocyte differentiation but may have a different ability to polarize macrophages.
Background: Mambalgin-2 is a snake venom peptide that blocks acid-sensing ion channels (ASICs) to relieve pain. Results: Mambalgin-2 interacts with at least three different regions of ASICs and exerts both stimulatory and inhibitory effects. Conclusion: Binding of mambalgin-2 into the pH sensor traps the channels in the closed conformation. Significance: This might allow development of optimized blockers of ASICs of therapeutic value.
Guanine nucleotide exchange factors (GEFs) of the exchange factor for Arf6 (EFA6), brefeldin A-resistant Arf guanine nucleotide exchange factor (BRAG), and cytohesin subfamilies activate small GTPases of the Arf family in endocytic events. These ArfGEFs carry a pleckstrin homology (PH) domain in tandem with their catalytic Sec7 domain, which is autoinhibitory and supports a positive feedback loop in cytohesins but not in BRAGs, and has an as-yet unknown role in EFA6 regulation. In this study, we analyzed how EFA6A is regulated by its PH and C terminus (Ct) domains by reconstituting its GDP/GTP exchange activity on membranes. We found that EFA6 has a previously unappreciated high efficiency toward Arf1 on membranes and that, similar to BRAGs, its PH domain is not autoinhibitory and strongly potentiates nucleotide exchange on anionic liposomes. However, in striking contrast to both cytohesins and BRAGs, EFA6 is regulated by a negative feedback loop, which is mediated by an allosteric interaction of Arf6-GTP with the PH-Ct domain of EFA6 and monitors the activation of Arf1 and Arf6 differentially. These observations reveal that EFA6, BRAG, and cytohesins have unanticipated commonalities associated with divergent regulatory regimes. An important implication is that EFA6 and cytohesins may combine in a mixed negative-positive feedback loop. By allowing EFA6 to sustain a pool of dormant Arf6-GTP, such a circuit would fulfill the absolute requirement of cytohesins for activation by Arf-GTP before amplification of their GEF activity by their positive feedback loop.endocytosis | membrane traffic | kinetics | autoinhibition
Members of the Arf family of small G proteins are involved in membrane traffic and organelle structure. They control the recruitment of coat proteins, and modulate the structure of actin filaments and the lipid composition of membranes. The ADP-ribosylation factor 6 (Arf6) isoform and the exchange factor for Arf6 (EFA6) are known to regulate the endocytic pathway of many different receptors. To determine the molecular mechanism of the EFA6/Arf6 function in vesicular transport, we searched for new EFA6 partners. In a twohybrid screening using the catalytic Sec7 domain as a bait, we identified endophilin as a new partner of EFA6. Endophilin contains a Bin/Amphiphysin/Rvs (BAR) domain responsible for membrane bending, and an SH3 domain responsible for the recruitment of dynamin and synaptojanin, two proteins involved, respectively, in the fission and uncoating of clathrin-coated vesicles. By using purified proteins, we confirmed the direct interaction, and identified the N-BAR domain as the binding motif to EFA6A. We showed that endophilin stimulates the catalytic activity of EFA6A on Arf6. In addition, we observed that the Sec7 domain competes with flat but not with highly curved lipid membranes to bind the N-BAR. In cells, expression of EFA6A recruits endophilin to EFA6A-positive plasma membrane ruffles, whereas expression of endophilin rescues the EFA6A-mediated inhibition of transferrin internalization. Overall, our results support a model whereby EFA6 recruits endophilin on flat areas of the plasma membrane to control Arf6 activation and clathrin-mediated endocytosis.small GTP-binding proteins | membrane curvature | vesicular trafficking T he ADP ribosylation factor family, which includes six members, is known to regulate different stages of vesicular trafficking (reviewed in refs. 1, 2). The most abundant isoform, Arf1, controls the membrane trafficking at the level of the Golgi apparatus by regulating in a GTP-dependent manner the recruitment of the COPI coat complex (3-5) and the two clathrin adaptors AP-1 (6, 7) and GGAs (8) onto the Golgi membranes. By activating lipid-modifying enzymes, Arf1 is able to change the lipid composition of the donor compartment membrane, thus facilitating membrane dynamic (9-12). ADP-ribosylation factor 6 (Arf6), the most distant isoform, is thought to regulate plasma membrane and endosomal trafficking. Similarly to Arf1, Arf6 activates the PLD (13, 14) and the type I PI4P5K (15, 16) to produce, respectively, phosphatidic acid, which is a fusogenic lipid, and phosphatidylinositol 4-5 bisphosphate, which is known to regulate clathrin-dependent endocytosis. Arf6 and PIP 2 cooperate (at least in vitro) to recruit AP-2 onto lipid membranes, suggesting a role for Arf6 in the formation of clathrin-coated pits (17). In addition to this putative role during the initial steps of internalization, Arf6 has been shown to interact and recruit Nm23-H1, a protein believed to control the dynamin-dependent fission of endocytic vesicles (18). These different observations have clarified the mole...
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