Late endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and type I IFN production in macrophages.
Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune diseases. In contrast, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the redistribution have not been fully elucidated. Ras related in brain (Rab)7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation. In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-alpha, IL-6, and IFN-beta in macrophages by impairing activation of MAPKs and NF-kappaB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
Yao
Ming
M
Institute of Immunology and Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, China.
Liu
Xingguang
X
Li
Dong
D
Chen
Taoyong
T
Cai
Zhen
Z
Cao
Xuetao
X
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation; D011992:Endosomes; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis*; D008247:Lysosomes; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D055550:Protein Stability; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000276:immunology* / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000090802:rab7 GTP-Binding Proteins
D016207:Cytokines; D007370:Interferon Type I; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D000090802:rab7 GTP-Binding Proteins; D020691:rab GTP-Binding Proteins