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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.
IMMUNOBIOLOGY Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR41 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)-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
, 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. 
