Please use this identifier to cite or link to this item: http://hdl.handle.net/10773/27856
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dc.contributor.authorPerego, Jessicapt_PT
dc.contributor.authorMendes, Andreiapt_PT
dc.contributor.authorBourbon, Clarissept_PT
dc.contributor.authorCamosseto, Voahiranapt_PT
dc.contributor.authorCombes, Alexispt_PT
dc.contributor.authorHong Liupt_PT
dc.contributor.authorManh, Thien-Phong Vupt_PT
dc.contributor.authorDalet, Alexandrept_PT
dc.contributor.authorChasson, Lionelpt_PT
dc.contributor.authorSpinelli, Lionelpt_PT
dc.contributor.authorBardin, Nathaliept_PT
dc.contributor.authorChiche, Laurentpt_PT
dc.contributor.authorSantos, Manuel A. S.pt_PT
dc.contributor.authorGatti, Evelinapt_PT
dc.contributor.authorPierre, Philippept_PT
dc.date.accessioned2020-03-09T18:22:16Z-
dc.date.available2020-03-09T18:22:16Z-
dc.date.issued2018-01-23-
dc.identifier.issn1945-0877pt_PT
dc.identifier.urihttp://hdl.handle.net/10773/27856-
dc.description.abstractEndoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, guanabenz protected mice from CpG oligonucleotide-dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that guanabenz and similar compounds could be used to treat type I IFN-dependent pathologies and that CH25H could be a therapeutic target to control these diseases.pt_PT
dc.language.isoengpt_PT
dc.publisherAmerican Association for the Advancement of Sciencept_PT
dc.relationDEQ20140329536pt_PT
dc.relationANR-12-BSV2-0025-01pt_PT
dc.relationANR-FCT 12-ISV3-0002-01pt_PT
dc.relationANR-11-LABEX-0054pt_PT
dc.relationANR-11-LABEX-0043pt_PT
dc.relationANR-10-IDEX-0001-02 PSLpt_PT
dc.relationANR-11-IDEX-0001-02pt_PT
dc.relationinfo:eu-repo/grantAgreement/FCT/5876/147343/PTpt_PT
dc.relationPTDC/IMI-IMU/3615/2014pt_PT
dc.relationEDSVS062pt_PT
dc.relationANR-10-INBS-04-01pt_PT
dc.rightsopenAccesspt_PT
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleGuanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complexpt_PT
dc.typearticlept_PT
dc.description.versionpublishedpt_PT
dc.peerreviewedyespt_PT
degois.publication.issue514pt_PT
degois.publication.titleScience Signalingpt_PT
degois.publication.volume11pt_PT
dc.identifier.doi10.1126/scisignal.aam8104pt_PT
dc.identifier.essn1937-9145pt_PT
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