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G[alpha]^sub i1^ and G[alpha]^sub i3^ regulate macrophage polarization by forming a complex containing CD14 and Gab1

Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα...) are required for LPS responses remains unclear, and if so, the underlying mechani...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2015-04, Vol.112 (15), p.4731
Main Authors: Li, Xianjing, Wang, Duowei, Chen, Zhen, Lu, Ermei, Wang, Zhuo, Duan, Jingjing, Tian, Wei, Wang, Yun, You, Linjun, Zou, Yulian, Cheng, Yan, Zhu, Qingyi, Wan, Xiaojian, Xi, Tao, Birnbaumer, Lutz, Yang, Yong
Format: Article
Language:English
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Summary:Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα...) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gα... form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gα... deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gα... knockdown in bone marrow-derived macrophage cells (Gα... KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gα... deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gα... were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gα... can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0027-8424
1091-6490