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Scaffolding adaptor protein Gab1 is required for TLR3/4- and RIG-I-mediated production of proinflammatory cytokines and type I IFN in macrophages.
J Immunol 2010; 184(11):6447-56JI

Abstract

RIG-I-like helicases and TLRs are critical sensors in the induction of type I IFN and proinflammatory cytokines to initiate innate immunity against invading pathogens. However, the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated. Grb2-associated binder 1 (Gab1), a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors, however, whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remain unknown. In this study, we demonstrated that Gab1 significantly enhances TLR4-, TLR3-, and RIG-I-triggered IL-6, IL-1beta, and IFN-alpha/beta production in macrophages. Gab1 knockdown in primary macrophages or Gab1 deficiency in mouse embryonic fibroblasts significantly suppresses TLR3/4- and RIG-I-triggered production of IL-6, IL-1beta, and IFN-alpha/beta. Consistently, Gab1 deficiency impairs vesicular stomatitis virus (VSV) infection-induced IFN-alpha/beta production. In addition to promoting both MyD88- and TLR/IL-1 receptor domain-containing adaptor protein inducing IFN-beta-dependent MAPKs and NF-kappaB activation, Gab1 enhances PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection. Accordingly, Gab1 inhibits VSV replication and VSV infection-induced cell damage by inducing type I IFNs and IFN-inducible gene expression via PI3K/Akt pathway. Therefore, Gab1 is needed for full activation of TLR3/4- and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs, and NF-kappaB pathways.

Authors+Show Affiliations

Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20435932

Citation

Zheng, Yuejuan, et al. "Scaffolding Adaptor Protein Gab1 Is Required for TLR3/4- and RIG-I-mediated Production of Proinflammatory Cytokines and Type I IFN in Macrophages." Journal of Immunology (Baltimore, Md. : 1950), vol. 184, no. 11, 2010, pp. 6447-56.
Zheng Y, An H, Yao M, et al. Scaffolding adaptor protein Gab1 is required for TLR3/4- and RIG-I-mediated production of proinflammatory cytokines and type I IFN in macrophages. J Immunol. 2010;184(11):6447-56.
Zheng, Y., An, H., Yao, M., Hou, J., Yu, Y., Feng, G., & Cao, X. (2010). Scaffolding adaptor protein Gab1 is required for TLR3/4- and RIG-I-mediated production of proinflammatory cytokines and type I IFN in macrophages. Journal of Immunology (Baltimore, Md. : 1950), 184(11), pp. 6447-56. doi:10.4049/jimmunol.0901750.
Zheng Y, et al. Scaffolding Adaptor Protein Gab1 Is Required for TLR3/4- and RIG-I-mediated Production of Proinflammatory Cytokines and Type I IFN in Macrophages. J Immunol. 2010 Jun 1;184(11):6447-56. PubMed PMID: 20435932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Scaffolding adaptor protein Gab1 is required for TLR3/4- and RIG-I-mediated production of proinflammatory cytokines and type I IFN in macrophages. AU - Zheng,Yuejuan, AU - An,Huazhang, AU - Yao,Ming, AU - Hou,Jin, AU - Yu,Yizhi, AU - Feng,Gensheng, AU - Cao,Xuetao, Y1 - 2010/04/30/ PY - 2010/5/4/entrez PY - 2010/5/4/pubmed PY - 2010/6/15/medline SP - 6447 EP - 56 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 184 IS - 11 N2 - RIG-I-like helicases and TLRs are critical sensors in the induction of type I IFN and proinflammatory cytokines to initiate innate immunity against invading pathogens. However, the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated. Grb2-associated binder 1 (Gab1), a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors, however, whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remain unknown. In this study, we demonstrated that Gab1 significantly enhances TLR4-, TLR3-, and RIG-I-triggered IL-6, IL-1beta, and IFN-alpha/beta production in macrophages. Gab1 knockdown in primary macrophages or Gab1 deficiency in mouse embryonic fibroblasts significantly suppresses TLR3/4- and RIG-I-triggered production of IL-6, IL-1beta, and IFN-alpha/beta. Consistently, Gab1 deficiency impairs vesicular stomatitis virus (VSV) infection-induced IFN-alpha/beta production. In addition to promoting both MyD88- and TLR/IL-1 receptor domain-containing adaptor protein inducing IFN-beta-dependent MAPKs and NF-kappaB activation, Gab1 enhances PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection. Accordingly, Gab1 inhibits VSV replication and VSV infection-induced cell damage by inducing type I IFNs and IFN-inducible gene expression via PI3K/Akt pathway. Therefore, Gab1 is needed for full activation of TLR3/4- and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs, and NF-kappaB pathways. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/20435932/Scaffolding_adaptor_protein_Gab1_is_required_for_TLR3/4__and_RIG_I_mediated_production_of_proinflammatory_cytokines_and_type_I_IFN_in_macrophages_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=20435932 DB - PRIME DP - Unbound Medicine ER -