title: Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway.
abstract: BACKGROUND
  The adapter proteins Appl1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif 1) and Appl2 are highly homologous and involved in several signaling pathways. While previous studies have shown that Appl1 plays a pivotal role in adiponectin signaling and insulin secretion, the physiological functions of Appl2 are largely unknown.
  
  
  RESULTS
  In the present study, the role of Appl2 in sepsis shock was investigated by using Appl2 knockout (KO) mice. When challenged with lipopolysaccharides (LPS), Appl2 KO mice exhibited more severe symptoms of endotoxin shock, accompanied by increased production of proinflammatory cytokines. In comparison with the wild-type control, deletion of Appl2 led to higher levels of TNF-α and IL-1β in primary macrophages. In addition, phosphorylation of Akt and its downstream effector NF-κB was significantly enhanced. By co-immunoprecipitation, we found that Appl2 and Appl1 interacted with each other and formed a complex with PI3K regulatory subunit p85α, which is an upstream regulator of Akt. Consistent with these results, deletion of Appl1 in macrophages exhibited characteristics of reduced Akt activation and decreased the production of TNFα and IL-1β when challenged by LPS.
  
  
  CONCLUSIONS
  Results of the present study demonstrated that Appl2 is a critical negative regulator of innate immune response via inhibition of PI3K/Akt/NF-κB signaling pathway by forming a complex with Appl1 and PI3K.
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Liufeng
authors.initials: L
authors.lastname: Mao
authors.affiliation: School of Life Sciences, Guangxi Normal University, Guilin, 541004 China ; Lab for Stem Cell and Pharmaceutical Biotechnology of Guangxi Normal University, Guilin, 541004 China.
authors.forename: Wanhua
authors.initials: W
authors.lastname: Lin
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Tao
authors.initials: T
authors.lastname: Nie
authors.affiliation: State key laboratory of pharmaceutical biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, 999077 China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hui
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, CB10 1SA UK.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Kuai
authors.initials: K
authors.lastname: Li
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Ding
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tang
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: State key laboratory of pharmaceutical biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, 999077 China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State key laboratory of pharmaceutical biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, 999077 China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, CB10 1SA UK.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
keywords: Akt; Appl1; Appl2; Endotoxin shock; Inflammatory cytokines; NF-κB; PI3K