title: SIRT1 links CIITA deacetylation to MHC II activation.
abstract: Antigen-dependent stimulation of T cells plays a critical role in adaptive immunity and host defense. Activation of major histocompatibility complex II (MHC II) molecules, dictated by Class II transactivator (CIITA), is considered a pivotal step in this process. The mechanism underlying differential regulation of CIITA activity by the post-translational modification machinery (PTM) and its implications are not clearly appreciated. Here, we report that SIRT1, a type III deacetylase, interacts with and deacetylates CIITA. SIRT1 activation augments MHC II transcription by shielding CIITA from proteasomal degradation and promoting nuclear accumulation and target binding of CIITA. In contrast, depletion of SIRT1 upregulates CIITA acetylation and attenuates its activity. Nicotinamide phosphoribosyltransferase (NAMPT) that synthesizes NAD(+) required for SIRT1 activation exerts similar effects on CIITA activity. Two different types of stress stimuli, hypobaric hypoxia and oxidized low-density lipoprotein (oxLDL), induce the acetylation of CIITA and suppress its activity by inhibiting the SIRT1 expression and activity. Thus, our data link SIRT1-mediated deacetylation of CIITA to MHC II transactivation in macrophages and highlight a novel strategy stress cues may employ to manipulate host adaptive immune system.
authors: State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors: Xiaoyan
authors: X
authors: Wu
authors: Xiaocen
authors: X
authors: Kong
authors: Dewei
authors: D
authors: Chen
authors: He
authors: H
authors: Li
authors: Yuhao
authors: Y
authors: Zhao
authors: Minjie
authors: M
authors: Xia
authors: Mingming
authors: M
authors: Fang
authors: Ping
authors: P
authors: Li
authors: Fei
authors: F
authors: Fang
authors: Lina
authors: L
authors: Sun
authors: Wenfang
authors: W
authors: Tian
authors: Huihui
authors: H
authors: Xu
authors: Yuyu
authors: Y
authors: Yang
authors: Xiaohong
authors: X
authors: Qi
authors: Yuqi
authors: Y
authors: Gao
authors: Jiahao
authors: J
authors: Sha
authors: Qi
authors: Q
authors: Chen
authors: Yong
authors: Y
authors: Xu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D005802:Genes, MHC Class II; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D008077:Lipoproteins, LDL; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; C099252:oxidized low density lipoprotein; D054409:Nicotinamide Phosphoribosyltransferase; D056564:Sirtuin 1