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Molecular and physiological roles of the adaptor protein CARD9 in immunity.

ABSTRACT: CARD9 is a caspase recruitment domain-containing signaling protein that plays a critical role in innate and adaptive immunity. It has been widely demonstrated that CARD9 adaptor allows pattern recognition receptors to induce NF-?B and MAPK activation, which initiates a "downstream" inflammation cytokine cascade and provides effective protection against microbial invasion, especially fungal infection. Here our aim is to update existing paradigms and summarize the most recent findings on the CARD9 signaling pathway, revealing significant mechanistic insights into the pathogenesis of CARD9 deficiency. We also discuss the effect of CARD9 genetic mutations on the in vivo immune response, and highlight clinical advances in non-infection inflammation.

SUBMITTER: Zhong X

PROVIDER: S-EPMC5833731 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Molecular and physiological roles of the adaptor protein CARD9 in immunity.

Zhong Xiaoming X Chen Bin B Yang Liang L Yang Zhiwen Z

Cell death & disease 20180119 2

CARD9 is a caspase recruitment domain-containing signaling protein that plays a critical role in innate and adaptive immunity. It has been widely demonstrated that CARD9 adaptor allows pattern recognition receptors to induce NF-κB and MAPK activation, which initiates a "downstream" inflammation cytokine cascade and provides effective protection against microbial invasion, especially fungal infection. Here our aim is to update existing paradigms and summarize the most recent findings on the CARD9 ...[more]

PMID: 29352133

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Project description:UNLABELLED:Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-?B and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies. IMPORTANCE:Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I-MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target.

Dataset Information

Molecular and physiological roles of the adaptor protein CARD9 in immunity.

Publications

Molecular and physiological roles of the adaptor protein CARD9 in immunity.

Similar Datasets

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