Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4.
Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-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)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, 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.
Wang
Yuzhen
Y
Institute of Immunology, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, P. R. China.
Chen
Taoyong
T
Han
Chaofeng
C
He
Donghua
D
Liu
Haibo
H
An
Huazhang
H
Cai
Zhen
Z
Cao
Xuetao
X
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D025801:Ubiquitin / Q000276:immunology / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D052118:Lysosomal-Associated Membrane Protein 1
D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D051907:Lysosomal Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009569:Nitric Oxide; D051197:Toll-Like Receptor 4; D025801:Ubiquitin; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C507780:Myd88 protein, mouse; C493487:Tlr4 protein, mouse