GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses

Chiang, Hao-Sen; Zhao, Yun; Song, Joo Hye; Liu, Song; Wang, Ninghai; Terhorst, Cox; Sharpe, Arlene H.; Basavappa, Megha; Jeffrey, Kate L.; Reinecker, Hans Christian

doi:10.1038/ni.2766

Cited by 38 publications

(62 citation statements)

References 50 publications

(72 reference statements)

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“…Notably, we found that BTN3A1 controls the TBK1-IRF3 axis activated by viral nucleic acids in the cytosol but not in the endosome, suggesting that sensing cytosolic nucleic acids drives BTN3A1 toward a functional form to initiate regulation. A few reports have described a link between microtubules and innate immunity (16,25). Our study shows that MAP4 regulates the dynein-based transport of BTN3A1 to the perinuclear region.…”

Section: Discussionmentioning

confidence: 59%

“…By contrast, cytoplasmic dynein is used to shuttle proteins to the minus end of the microtubule, as in the case of trafficking from the ER to the Golgi (15). The detection of nucleic acids in antiviral host defense seems to depend on microtubules bound to GEF-H1 (16). Given the relation between trafficking and type I IFN signaling, it is likely that the microtubuledependent transport of key components of the type I IFN signaling pathway is crucial for inducing antiviral immune responses.…”

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confidence: 99%

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MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

Seo

Lee

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA-and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid-or virus-triggered activation of IFN-β production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1-TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubuleassociated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA-or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling.BTN3A1 | type I IFN signaling | TBK1-IRF3 axis | MAP4 | dynein

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

Seo

Lee

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Two mitochondrial fusion protein, mitofusion 1 (MFN1) and MFN2, have been shown to regulate the mitochondrial-membrane potential for the optimal MAVS activation (Koshiba et al 2011 ). Focal adhesion kinase and a microtubule-associated guanine nucleotide exchange factor (GEF)-H1 were recently shown to participate in RLR signaling, suggesting a key role for the microtubule network in this regulation (Chiang et al 2014 ;Bozym et al 2012 ). These newly emerged RLR regulators underscore the intricate regulation of RLR signaling.…”

Section: Rig-i-like Receptor (Rlr) Sensing and Signalingmentioning

confidence: 96%

Emerging Roles of an Innate Immune Regulator TAPE in the Toll-Like Receptor and RIG-I-Like Receptor Pathways

Chen

Ling

2015

Inflammation and Immunity in Cancer

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Infl ammation alerts the mammalian immune system to defend pathogen invasion or to resolve tissue damage. Dysregulation of infl ammation contributes to the development of infectious diseases or infl ammation-mediated chronic diseases such as obesity, diabetes, atherosclerosis, and cancer. Pattern-recognition receptors (PRRs) and their downstream regulators in the innate immune system function to trigger infl ammation upon sensing molecular components from invading pathogens or damaged host cells. Better understanding of the regulation of PRR-mediated infl ammation provides critical insights toward developing the treatment of infectious diseases and chronic infl ammatory diseases. However, signaling networks underlying these PRR pathways still remain complicated and have much to be explored. Emerging evidence indicates that subcellular compartments or lipid organelles function as signaling platforms for conveying PRR signaling. Several cellular mediators of these subcellular organelles and vesicle traffi cking have emerged to regulate the PPR pathways. In this review, we fi rst highlight recent advances in the cell biology aspects of the Toll-like receptor (TLR) and cytosolic retinoic acid-inducible gene (RIG)-I-like receptor (RLR) pathways. We then focus on discussing a recently identifi ed innate immune regulator called TBK1-associated protein in the endolysosomes (TAPE), also known as CC2D1A/Freud-1/Aki-1.

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“…In fact, recent evidence suggests that MDA5 is not only required for lung innate immune responses to parainfluenza (26), but is also required for regulating chronic inflammation after infection (27). Recently, it was demonstrated that mice deficient in the guanine nucleotide exchange factor GEF-H1 were shown to lack RIG-I and MDA5-dependent phosphorylation of IRF3 and were more susceptible to lung infection with influenza A (28). Studies have also shown that some viruses have become adept at evading RIG-1 and MDA5-mediated events.…”

Section: Non-tlr Innate Immune Receptors Functioning In the Lungmentioning

confidence: 99%

Innate Receptors and Cellular Defense against Pulmonary Infections

Werner

Steele

2014

The Journal of Immunology

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In the United States, mortality as a result of lung infections consistently ranks in the top ten leading causes of death, accounting for over 50,000 deaths annually. Moreover, there are more than 140,000 deaths annually as a result of chronic lung diseases, some of which may be complicated by an infectious process. The lung is constantly exposed to the environment and consequently, susceptible to infectious complications caused by bacterial, viral, fungal and parasitic pathogens. Indeed, we are continually faced with the threat of morbidity and mortality associated with annual influenza virus infections, new respiratory viruses (such as SARS-CoV) as well as lung infections caused by antibiotic-resistant “ESKAPE pathogens” (three of which target the lung). This review will highlight innate immune receptors and cell types that function to protect against infectious challenges to the respiratory system yet may also be associated with exacerbations in chronic lung diseases.

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GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses

Cited by 38 publications

References 50 publications

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

Emerging Roles of an Innate Immune Regulator TAPE in the Toll-Like Receptor and RIG-I-Like Receptor Pathways

Innate Receptors and Cellular Defense against Pulmonary Infections

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