title: E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity.
abstract: The E2 polyubiquitin-conjugating enzyme Ubc13 is a mediator of innate immune reactions. Ubc13 mediates the conjugation of keratin (K)63-linked polyubiquitin chains onto TNF receptor-associated factor 6 and IKKγ during NF-κB activation. In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes. Although Ubc13 has been shown to be critical for Toll-like receptor (TLR) and IL-1 receptor signaling, the function of Ubc13 in the epidermis has not been studied. We generated keratinocyte-specific Ubc13-deficient mice (Ubc13(flox/flox)K5-Cre). At birth, the skin of the Ubc13(flox/flox)K5-Cre mice was abnormally shiny and smooth; in addition, the mice did not grow and died by postnatal day 2. Histological analysis showed atrophy of the epidermis with keratinocyte apoptosis. Immunohistochemical analyses revealed reduced proliferation, abnormal differentiation, and apoptosis of keratinocytes in the Ubc13(flox/flox)K5-Cre mouse epidermis. In culture, Ubc13(flox/flox)K5-Cre keratinocyte growth was impaired, and spontaneous cell death occurred. Moreover, the deletion of Ubc13 from cultured Ubc13(flox/flox) keratinocytes by means of an adenoviral vector carrying Cre recombinase also resulted in spontaneous cell death. Therefore, Ubc13 is essential for keratinocyte growth, differentiation, and survival. Analyses of intracellular signaling revealed that the IL-1 and TNF-induced activation of JNK, p38, and NF-κB pathways was impaired in Ubc13(flox/flox)K5-Cre keratinocytes. In conclusion, Ubc13 appears to be essential for epidermal integrity in mice.
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan. sayama@m.ehime-u.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.forename: Myoung-Sook
authors.initials: MS
authors.lastname: Shin
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004817:Epidermis / Q000276:immunology / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D007633:Keratins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D007633:Keratins; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D051550:I-kappa B Kinase