Browsing by Author "Cavadas, Miguel"
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- Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesisPublication . Badenes, Marina; Amin, Abdulbasit; González-García, Ismael; Félix, Inês; Burbridge, Emma; Cavadas, Miguel; Ortega, Francisco José; de Carvalho, Érika; Faísca, Pedro; Carobbio, Stefania; Seixas, Elsa; Pedroso, Dora; Neves-Costa, Ana; Moita, Luís F.; Fernández-Real, José Manuel; Vidal-Puig, António; Domingos, Ana; López, Miguel; Adrain, ColinObjective: Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome. Methods: We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration. Results: Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced ther- mogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.
- iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACEPublication . Oikonomidi, Ioanna; Burbridge, Emma; Cavadas, Miguel; Sullivan, Graeme; Collis, Blanka; Naegele, Heike; Clancy, Danielle; Brezinova, Jana; Hu, Tianyi; Bileck, Andrea; Gerner, Christopher; Bolado, Alfonso; Kriegsheim, Alex Von; Martin, Seamus J.; Steinberg, FlorianThe apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.
- Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACEPublication . Cavadas, Miguel; Oikonomidi, Ioanna; Gaspar, Catarina J.; Burbridge, Emma; Badenes, Marina; Félix, Inês; Bolado, Alfonso; Hu, Tianyi; Bileck, Andrea; Gerner, Christopher; Domingos, Pedro M.; von Kriegsheim, Alex; Adrain, ColinCell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.
- Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACEPublication . Cavadas, Miguel; Oikonomidi, Ioanna; Gaspar, Catarina J.; Burbridge, Emma; Badenes, Marina; Félix, Inês; Bolado, Alfonso; Hu, Tianyi; Bileck, Andrea; Gerner, Christopher; Domingos, Pedro M.; von Kriegsheim, Alex; Adrain, ColinCell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.