title: A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2.
abstract: The association between hyperinflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, nontranscriptional role of GPS2 as a guardian against hyperstimulation of the TNF-α-induced gene program. GPS2 cytoplasmic actions are required to specifically modulate RIP1 ubiquitylation and JNK activation by inhibiting TRAF2/Ubc13 enzymatic activity. In vivo relevance of GPS2 anti-inflammatory role is confirmed by inhibition of TNF-α target genes in macrophages and by improved insulin signaling in the adipose tissue of aP2-GPS2 transgenic mice. As the nontranscriptional role is complemented by GPS2 functioning as positive and negative cofactor for nuclear receptors, in vivo overexpression also results in elevated circulating level of Resistin and development of hepatic steatosis. Together, these studies define GPS2 as a molecular guardian required for precise control of inflammatory responses involved in immunity and homeostasis.
authors.affiliation: Howard Hughes Medical Institute, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: M Dafne
authors.initials: MD
authors.lastname: Cardamone
authors.forename: Anna
authors.initials: A
authors.lastname: Krones
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tanasa
authors.forename: Havilah
authors.initials: H
authors.lastname: Taylor
authors.forename: Laura
authors.initials: L
authors.lastname: Ricci
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Valentina
authors.initials: V
authors.lastname: Perissi
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D052243:Resistin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
chemical_list: C572597:GPS2 protein, mouse; D020690:GTPase-Activating Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C490620:Ralbp1 protein, mouse; D052243:Resistin; C499623:Retn protein, mouse; D014409:Tumor Necrosis Factor-alpha; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D048670:MAP Kinase Kinase 4