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Blood, 1 August 2007, Vol. 110, No. 3, pp. 962-971. Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2007-01-066027. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-01-066027v1 110/3/962    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Cao, X. Related Collections Immunobiology Phagocytes Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 Yuzhen Wang1,2, Taoyong Chen2, Chaofeng Han2, Donghua He1, Haibo Liu2, Huazhang An2, Zhen Cai1, and Xuetao Cao1,2 1 Institute of Immunology, Zhejiang University, Hangzhou; 2 Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, People's Republic of China Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain–containing adapter, inducing interferon (IFN)-ß–dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-, IL-6, nitric oxide, and IFN-ß, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor B, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1–positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: TLR4 signaling: negative regulation by degradation Osamu Takeuchi and Shizuo Akira Blood 2007 110: 794. [Full Text] [PDF] This article has been cited by other articles: T. Zhang, S. Liu, P. Yang, C. Han, J. Wang, J. Liu, Y. Han, Y. Yu, and X. Cao Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/{beta}-catenin pathway Blood, November 5, 2009; 114(19): 4081 - 4088. [Abstract] [Full Text] [PDF] M. Yao, X. Liu, D. Li, T. Chen, Z. Cai, and X. Cao Late Endosome/Lysosome-Localized Rab7b Suppresses TLR9-Initiated Proinflammatory Cytokine and Type I IFN Production in Macrophages J. Immunol., August 1, 2009; 183(3): 1751 - 1758. [Abstract] [Full Text] [PDF] C. Han, T. Chen, M. Yang, N. Li, H. Liu, and X. Cao Human SCAMP5, a Novel Secretory Carrier Membrane Protein, Facilitates Calcium-Triggered Cytokine Secretion by Interaction with SNARE Machinery J. Immunol., March 1, 2009; 182(5): 2986 - 2996. [Abstract] [Full Text] [PDF] C. Wang, T. Chen, N. Zhang, M. Yang, B. Li, X. Lu, X. Cao, and C. Ling Melittin, a Major Component of Bee Venom, Sensitizes Human Hepatocellular Carcinoma Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by Activating CaMKII-TAK1-JNK/p38 and Inhibiting I{kappa}B{alpha} Kinase-NF{kappa}B J. Biol. Chem., February 6, 2009; 284(6): 3804 - 3813. [Abstract] [Full Text] [PDF] T. Chen, J. Guo, C. Han, M. Yang, and X. Cao Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway J. Immunol., February 1, 2009; 182(3): 1449 - 1459. [Abstract] [Full Text] [PDF] S. L. Schwartz, C. Cao, O. Pylypenko, A. Rak, and A. Wandinger-Ness Rab GTPases at a glance J. Cell Sci., November 15, 2007; 120(22): 3905 - 3910. [Full Text] [PDF]

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