title: The endoplasmic reticulum acts as a platform for ubiquitylated components of nuclear factor κB signaling.
abstract: The innate and adaptive immune responses involve the stimulation of nuclear factor κB (NF-κB) transcription factors through the Lys(63) (K(63))-linked ubiquitylation of specific components of NF-κB signaling pathways. We found that ubiquitylated components of the NF-κB pathway accumulated on the cytosolic leaflet of the endoplasmic reticulum (ER) membrane after the engagement of cell-surface, proinflammatory cytokine receptors or antigen receptors. Through mass spectrometric analysis, we found that the ER-anchored protein metadherin (MTDH) was a partner for these ubiquitylated activators of NF-κB and that it directly bound to K(63)-linked polyubiquitin chains. Knockdown of MTDH inhibited the accumulation of ubiquitylated NF-κB signaling components at the ER, reduced the extent of NF-κB activation, and decreased the amount of proinflammatory cytokines produced. Our observations highlight an unexpected facet of the ER as a key subcellular gateway for NF-κB activation.
authors.affiliation: INSERM, UMR_S 1014, Hôpital Paul Brousse, Villejuif 94800, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Alexia
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Poalas
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Naima
authors.initials: N
authors.lastname: Zemirli
authors.forename: Julie
authors.initials: J
authors.lastname: Dwyer
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Dubois
authors.forename: Emeline M
authors.initials: EM
authors.lastname: Hatchi
authors.forename: Nelia
authors.initials: N
authors.lastname: Cordeiro
authors.forename: Sherri S
authors.initials: SS
authors.lastname: Smith
authors.forename: Céline
authors.initials: C
authors.lastname: Castanier
authors.forename: Armelle
authors.initials: A
authors.lastname: Le Guelte
authors.forename: Liling
authors.initials: L
authors.lastname: Wan
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
authors.forename: Julie
authors.initials: J
authors.lastname: Gavard
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D019169:Jurkat Cells; D008565:Membrane Proteins; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D025821:Polyubiquitin / Q000235:genetics / Q000276:immunology*; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; C483039:MTDH protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D025821:Polyubiquitin