Activated macrophages play an important role in many inflammatory diseases including septic shock and atherosclerosis. However, the molecular mechanisms limiting macrophage inflammation are not completely understood. MCP-induced protein 1 (MCPIP1) is a recently identified CCCH-zinc finger containing protein, which was significantly induced by monocyte chemotactic protein 1 (MCP-1) and thus designated as MCPIP1. In our previous works, we have identified MCPIP1 as a novel negative regulator of macrophage inflammatory activation. In our recent studies, we have further found that MCPIP1 acts as a deubiquitinating enzyme that may negatively regulates NF-?B signaling by removing ubiquitin moieties from critical proteins, such as TNF receptor adaptor factors (TRAFs), RIP and I?B?. Consistently, MCPIP1- deficient mice spontaneously developed inflammatory syndrome and died prematurely. Macrophages from MCPIP1-/- mice showed high up-regulation of inflammatory gene expression, together with a greatly increased NF-?B activation, as well as increased polyubiquitination of TRAF2 and TRAF6. Furthermore, in vitro assay directly demonstrated the deubiquitinating activity of purified MCPIP1. Based on these intriguing findings, we hypothesize that MCPIP1 represses NF-kB signaling and microphage activation mainly through deubiquitination of TRAF family. The overall objective of this proposal is to test the central hypothesis by using combined biochemical and genetic approaches. Specially, we will establish MCPIP1- mediated deubiquitination of TRAFs as an essential mechanism in the regulation of NF-?B signaling as well as macrophage activation both in vitro and in vivo. We will attain the objective of this aim by using following approaches: 1) determine the direct molecular targets of MCPIP1 deubiquitinase in vitro;2) determine the in vivo targets of MCPIP1 deubiquitinase using the primary cells and tissues from MCPIP1 knockout mouse;3) map the active domain of MCPIP1 deubiquitinase through serial mutagenesis analysis; 4) define the functional relationship between deubiquitinase domain and RNase domain;5) determine the relative contribution of the deubiquitinase activity of MCPIP1 to the suppression of NF-?B signaling as well as macrophage activation;6) determine the role of MCPIP1 deubiquitinase in human macrophages. Completion of the proposed studies will not only help to understand the molecular basis of macrophage activation, but also implicate in the development of novel drug therapies against inflammatory diseases such as atherosclerosis.
The goal of this proposal is to explore the role and molecular mechanisms of a newly identified zinc finger protein MCPIP1 in regulating NF-KB signaling and macrophage activation. Completion of this research program will not only help us understand the function and molecular mechanisms of MCPIP1 in macrophage activation, but also provide critical information for potential new therapies for inflammatory diseases including atherosclerosis.
|Huang, Shengping; Miao, Ruidong; Zhou, Zhou et al. (2013) MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cell Signal 25:1228-34|
|Gu, Ling; Ning, Huan; Qian, Xuesong et al. (2013) Suppression of IL-12 production by tristetraprolin through blocking NF-kcyB nuclear translocation. J Immunol 191:3922-30|
|Qian, Xuesong; Gu, Ling; Ning, Huan et al. (2013) Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol 190:5894-902|
|Niu, Jixiao; Shi, Yuling; Xue, Jingyan et al. (2013) USP10 inhibits genotoxic NF-?B activation by MCPIP1-facilitated deubiquitination of NEMO. EMBO J 32:3206-19|
|Miao, Ruidong; Huang, Shengping; Zhou, Zhou et al. (2013) Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunol Cell Biol 91:368-76|
|Liu, Ling; Zhou, Zhou; Huang, Shengping et al. (2013) Zc3h12c inhibits vascular inflammation by repressing NF-ýýB activation and pro-inflammatory gene expression in endothelial cells. Biochem J 451:55-60|
|Zhou, Zhou; Miao, Ruidong; Huang, Shengping et al. (2013) MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms. PLoS One 8:e82542|
|Huang, Shengping; Qi, Dongfei; Liang, Jian et al. (2012) The putative tumor suppressor Zc3h12d modulates toll-like receptor signaling in macrophages. Cell Signal 24:569-76|
|Qi, Dongfei; Huang, Shengping; Miao, Ruidong et al. (2011) Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J Biol Chem 286:41692-700|
|Qi, Yongfen; Liang, Jian; She, Zhi-Gang et al. (2010) MCP-induced protein 1 suppresses TNFalpha-induced VCAM-1 expression in human endothelial cells. FEBS Lett 584:3065-72|
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