title: The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1.
abstract: Deficiency in the E3 ubiquitin ligase Itch causes a skin-scratching phenotype in mice. We found that there was increased phosphorylation and activation of the mitogen-activated protein kinase p38α in spontaneous and experimentally induced skin lesions of Itch-deficient (Itch-/-) mice. Itch bound directly to the TGF-β-activated kinase 1-binding protein 1 (Tab1) through a conserved PPXY motif and inhibited the activation of p38α. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38α phosphorylation exhibited by Itch-/- cells. Similarly, reconstitution of Itch-/- cells with wild-type Itch, but not the ligase-deficient Itch-C830A mutant, inhibited the phosphorylation and activation of p38α. Compared to the skin of wild-type mice, the skin of Itch-/- mice contained increased amounts of the mRNAs of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1β, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38α and Tab1 with a cell-permeable peptide substantially attenuated skin inflammation in Itch-/- mice. These findings provide insight into how Itch-mediated regulatory mechanisms prevent chronic skin inflammation, which could be exploited therapeutically.
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Balamayooran
authors.initials: B
authors.lastname: Theivanthiran
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kathania
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Minghui
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Anguiano
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Vandergriff
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden.
authors.forename: Ramin
authors.initials: R
authors.lastname: Massoumi
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA. venuprasad.poojary@baylorhealth.edu.
authors.forename: K
authors.initials: K
authors.lastname: Venuprasad
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C531463:Tab1 protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D048308:Mitogen-Activated Protein Kinase 14