title: Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3).
abstract: Interleukin-31 (IL-31) is a T helper type 2 cell-derived cytokine tightly associated with inflammatory skin disorders. IL-31-induced signaling is mediated by a receptor complex composed of oncostatin M receptor β and the cytokine-specific receptor subunit IL-31Rα, of which there are several isoforms. The latter can be classified as long or short isoforms with respect to their intracellular domain. At present, the signaling capabilities of the different isoforms remain inchoately understood, and potential mechanisms involved in negative regulation of IL-31Rα signaling have so far not been studied in detail. Here, we show that both the long and short isoforms of IL-31Rα are capable of inducing STAT signaling. However, the presence of a functional JAK-binding box within IL-31Rα is an essential prerequisite for functional IL-31-mediated STAT3 signaling. Moreover, both the long and short isoforms require oncostatin M receptor β for their activity. We also show that IL-31 induces expression of four suppressor of cytokine signaling family members and provide evidence that SOCS3 acts as a potent feedback inhibitor of IL-31-induced signaling. Taken together, this study identifies crucial requirements for IL-31 signaling and shows its counter-regulation by SOCS3.
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Elisabeth
authors: E
authors: Maier
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Michaela
authors: M
authors: Mittermeir
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Stefanie
authors: S
authors: Ess
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Theresa
authors: T
authors: Neuper
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Angela
authors: A
authors: Schmiedlechner
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Albert
authors: A
authors: Duschl
authors: From the Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria jutta.horejs_hoeck@sbg.ac.at.
authors: Jutta
authors: J
authors: Horejs-Hoeck
mesh_terms: D020816:Amino Acid Motifs; D002462:Cell Membrane / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D053681:Oncostatin M Receptor beta Subunit / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: C502187:IL31 protein, human; C502188:IL31RA protein, human; D007378:Interleukins; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D020033:Protein Isoforms; D018123:Receptors, Interleukin; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine
keywords: IL-31 signaling; IL-31R α isoforms; OSMR β; STAT3; feedback inhibition; interleukin; receptor; signal transduction; suppressor of cytokine signaling 3 (SOCS3); suppressors of cytokine signaling 1 (SOCS1)