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Posttranslational Modification Cross Talk Regulates the Critical Adaptive Immune Molecule, The Class II Transactivator
Author(s) -
Morgan Julie,
Greer Susanna
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.570.11
Subject(s) - ciita , pcaf , ubiquitin ligase , transactivation , ubiquitin , phosphorylation , microbiology and biotechnology , biology , acetylation , histone , immune system , cancer research , transcription factor , major histocompatibility complex , mhc class ii , genetics , gene
Major histocompatibility class II (MHC II) molecules present pathogenic and tumorigenic antigens to CD4 + T cells and play vital roles in regulating adaptive immune responses. MHC II is controlled at the level of transcription by the Class II Transactivator (CIITA), which in turn is regulated through a series of posttranslational modifications (PTMs). Acetylation of CIITA by the histone acetyltransferase (HAT) pCAF, results in CIITA nuclear localization. CIITA is also phosphorylated by Extracellular Signal Regulated Kinase (ERK1/2) at S280, a critical site for regulating additional PTMs such as mono‐ubiquitination. Both phosphorylation and mono‐ubiquitination is key in CIITA's stability and increased transactivation. We have identified that phosphorylation of CIITA by ERK1/2 enhances K63 linked ubiquitination leading to CIITA's ability to bind to the MHC II promoter. pCAF was recently identified as an E3 ligase for the nuclear protein Mdm2. We show here pCAF increases both CIITA transactivation and ubiquitination; suggesting pCAF also plays a role in regulating CIITA ubiquitination whether through its HAT or E3 ligase capability has yet to be elucidated. These data provide novel links between acetylation, phosphorylation and ubiquitination of this critical inflammatory protein. Our data suggests particular posttranslational modifications of CIITA result in very different functional outcomes, and may enable the identification of biomarkers for immune diseases associated with dysregulated antigen presentation. Support for research provided by Molecular Basis of Disease area of Focus, Georgia State University