title: The class II transactivator (CIITA) is regulated by post-translational modification cross-talk between ERK1/2 phosphorylation, mono-ubiquitination and Lys63 ubiquitination.
abstract: The class II transactivator (CIITA) is known as the master regulator for the major histocompatibility class II (MHC II) molecules. CIITA is dynamically regulated through a series of intricate post-translational modifications (PTMs). CIITA's role is to initiate transcription of MHC II genes, which are responsible for presenting extracellular antigen to CD4(+) T-cells. In the present study, we identified extracellular signal-regulated kinase (ERK)1/2 as the kinase responsible for phosphorylating the regulatory site, Ser(280), which leads to increased levels of mono-ubiquitination and an overall increase in MHC II activity. Further, we identify that CIITA is also modified by Lys(63)-linked ubiquitination. Lys(63) ubiquitinated CIITA is concentrated in the cytoplasm and following activation of ERK1/2, CIITA phosphorylation occurs and Lys=ubiquitinated CIITA translocates to the nucleus. CIITA ubiquitination and phosphorylation perfectly demonstrates how CIITA location and activity is regulated through PTM cross-talk. Identifying CIITA PTMs and understanding how they mediate CIITA regulation is necessary due to the critical role CIITA has in the initiation of the adaptive immune response.
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, Georgia 30302, U.S.A.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Morgan
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, Georgia 30302, U.S.A.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Shanderson
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, Georgia 30302, U.S.A.
authors.forename: Nathaniel H
authors.initials: NH
authors.lastname: Boyd
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, Georgia 30302, U.S.A.
authors.forename: Ercan
authors.initials: E
authors.lastname: Cacan
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, Georgia 30302, U.S.A. sgreer@gsu.edu.
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Greer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D048052:Mitogen-Activated Protein Kinase 3
keywords: immunology; protein regulation; transcription regulation