Blood：曹雪涛院士发现新型Rab蛋白在TLR4信号传导中的作用

生物谷

之前的研究发现TLR4诱导髓样分化因子88（myeloid differentiation factor 88，MyD88）依赖性，和Toll/interleukin (IL)-1R位点包含adapter，诱导干扰素ß依赖性信号（interferon (IFN)-ß–dependent signaling），从而导致炎症前介导子和I型干扰素的产生

来抵制病原体。

但是未得以控制的TLR4激活也许会导致自身免疫（autoimmune）性疾病和炎症疾病的发生。TLR4从血浆膜（plasma membrane）传送到内体(endosome)，帮助泛素化（ubiqutination），和传送到溶酶体（lysosome）中，用以降解。TLR4表达的降低，或者TLR4降解的增多对于TLR4信号途径而言是十分重要的。

曹雪涛教授等人之前的研究发现了一个溶酶体相关的小鸟嘌呤核甘三磷酸酶（small guanosine triphosphatase，GTPase），而王玉珍等人之前研究围绕着新型的Rab蛋白——Rab7，这种蛋白7定位于溶酶体，调控蛋白从早期内体到晚期内体或晚期内体到溶酶体的转运。

近年来的研究表明，Rab7参与多种受体的转运及信号转导过程。他们自主克隆到的一个新的小G蛋白：Rab7b，与Rab7高度同源，也定位于溶酶体，特异性地表达在单核细胞系。

TLRs主要分布在单核细胞如巨噬细胞和树突状细胞，因此设想Rab7b可能参与TLRs的信号转导。之前的课题中，他们研究了小G蛋白mRab7b在巨噬细胞TLRs信号转导中的调控作用。

在这篇文章中，研究人员证明了Rab7b可以通过促进TLR4的降解负调控许多因子，包括脂多糖诱导的肿瘤坏死因子（tumor necrosis factor，TNF），IL-6，一氧化氮，IFN-ß，以及LPS诱导的丝裂素（mitogen）激活蛋白激酶，细胞核因子Rab7bB，IFN调控因子3信号途径。

并且Rab7b定位在LAMP-1阳性亚细胞室中，在施用了LPS治疗后与TLR4共定位，降解TLR4的蛋白质水平，这些说明Rab7b是TLR4信号途径的负调控因子，功能是促进TLR4转移至溶酶体降解。

原始出处:

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 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)- ${alpha}$ , IL-6, nitric oxide, and IFN-ß, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor ${kappa}$ 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.