title: Class II transactivator (CIITA) mediates transcriptional repression of pdk4 gene by interacting with hypermethylated in cancer 1 (HIC1).
abstract: Increased accumulation and/or impaired utilization of fatty acid in extra-adipose tissues are implicated in the pathogenesis of insulin resistance and type 2 diabetes. Pyruvate dehydrogenase kinase 4 (Pdk4) is a key enzyme involved in fatty oxidation and energy expenditure, and its expression can be repressed by pro-inflammatory stimuli. Previously, we have shown that class II transactivator (CIITA) mediates the adverse effect of interferon gamma (IFN-γ) in skeletal muscle cells by cooperating with hypermethylated in cancer 1 (HIC1) to repress silent information regulator 1 (SIRT1) transcription. Building upon this finding, we report here that CIITA interacted with HIC1 via the GTP-binding domain (GBD) while HIC1 interacted with CIITA via the BTB/POZ domain. The GBD domain was required for CIITA to repress SIRT1 transcription probably acting as a bridge for CIITA to bind to HIC1 and consequently to bind to the SIRT1 promoter. IFN-γ stimulation, CIITA over-expression, or HIC1 over-expression repressed Pdk4 promoter activity while silencing either CIITA or HIC1 normalized Pdk4 expression in the presence of IFN-γ. An increase in SIRT1 expression or activity partially rescued Pdk4 expression in the presence of CIITA, but SIRT1 inhibition abrogated Pdk4 normalization even in the absence of CIITA. Taken together, our data have identified a HIC1-CIITA-SIRT1 axis that regulates Pdk4 transcription in response to IFN-γ stimulation.
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology.|Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, Jiangsu 210029, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology.|Department of Gastroenterology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology.|Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China. wxy@njmu.edu.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology.|Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China. yjxu@njmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
keywords: CIITA; HIC; IFN gamma; PDK4; SIRT1; transcriptional regulation