NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses

Guo, Haitao; König, Renate; Deng, Meng; Rieß, Maximilian; Mo, Jinyao; Zhang, Lu; Petrucelli, Alex; Yoh, Sunnie M.; Barefoot, Brice E.; Samo, M. U.; Sempowski, Gregory D.; Zhang, Aiping; Colberg-Poley, Anamaris M.; Feng, Hui; Lemon, Stanley M.; Liu, Yong; Zhang, Yanping; Wen, Haitao; Zhang, Zhigang; Damania, Blossom; Tsao, Li-Chung; Wang, Qi; Su, Lishan; Duncan, Joseph A.; Chanda, Sumit K.; Ting, Jenny P.-Y.

doi:10.1016/j.chom.2016.03.001

Cited by 133 publications

(136 citation statements)

References 47 publications

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“…Furthermore, NLRX1 has been demonstrated to inhibit STING signalling by blocking the interaction between STING and TANK-binding kinase 1 (TBK1), which is required for the induction of IFN-1 in response to DNA. Moreover, NLRX1 -/-cells express a higher level of type 1 interferon during HIV-1 infection or treatment with cyclic GAMP or cyclic di-GMP, which triggers STING-dependent responses [109]. However, NLRX1 regulation is quite complex and seems to occur via cell typeand signal-dependent mechanisms; the above findings suggest the role of NLRX1 in the regulation of IFN during viral infection as well as the regulation and activation of inflammasomes.…”

Section: Nlrx1mentioning

confidence: 96%

Inflammasomes and its importance in viral infections

León-Juárez²,

et al. 2016

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A complex interplay between pathogen and host determines the immune response during viral infection. A set of cytosolic sensors are expressed by immune cells to detect viral infection. NOD-like receptors (NLRs) comprise a large family of intracellular pattern recognition receptors. Members of the NLR family assemble into large multiprotein complexes, termed inflammasomes, which induce downstream immune responses to specific pathogens, environmental stimuli, and host cell damage. Inflammasomes are composed of cytoplasmic sensor molecules such as NLRP3 or absent in melanoma 2 (AIM2), the adaptor protein ASC (apoptosis-associated speck-like protein containing caspase recruitment domain), and the effector protein procaspase-1. The inflammasome operates as a platform for caspase-1 activation, resulting in caspase-1-dependent proteolytic maturation and secretion of interleukin (IL)-1b and IL-18. This, in turn, activates the expression of other immune genes and facilitates lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Moreover, inflammasomes counter viral replication and remove infected immune cells through an inflammatory cell death, program termed as pyroptosis. As a countermeasure, viral pathogens have evolved virulence factors to antagonise inflammasome pathways. In this review, we discuss the role of inflammasomes in sensing viral infection as well as the evasion strategies that viruses have developed to evade inflammasome-dependent immune responses. This information summarises our understanding of host defence mechanisms against viruses and highlights research areas that can provide new approaches to interfere in the pathogenesis of viral diseases.

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Section: Nlrx1mentioning

confidence: 96%

Inflammasomes and its importance in viral infections

León-Juárez²,

et al. 2016

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“…NLRC3 interacts with both STING and TBK1 and disturbs STING translocation and STING-TBK1 association to block type I IFN production (49). Interestingly, NLRX1 also inhibits the STING-mediated signaling pathway by impeding the STING-TBK1 interaction (29). The mechanism discovered in the present study, where NLRX1 attenuates virus-induced IFN signaling by targeting MAVS for degradation, presents a new perspective for understanding the action of the host innate immune system.…”

Section: Discussionmentioning

confidence: 62%

“…Although evidence from a recent report indicated that NLRX1 may act as a proviral host factor in infection by human immunodeficiency virus type 1 and some DNA viruses (29), the role of NLRX1 in HCV infection remains obscure. To investigate whether NLRX1 modulates HCV propagation, we constructed a stable NLRX1-silenced cell line using HLCZ01 cells, which support the entire life cycle of HCV (see details in our previous study [33]).…”

Section: Resultsmentioning

confidence: 99%

“…Some studies suggested that NLRX1 is capable of negatively regulating the innate immune response through blocking IFN and cytokine production pathways (26)(27)(28)(29). However, another study reported that NLRX1 enhances antiviral activity (34).…”

Section: Resultsmentioning

confidence: 99%

“…Unlike other NLRs, NLRX1 does not exhibit inflammasome functions and has unique functions in immune modulation, autophagy, and tumorigenesis. NLRX1 attenuates IRF3 and NF-B signaling pathways in response to viral infection and TLR activation (26)(27)(28)(29). Furthermore, NLRX1 promotes virus-induced autophagy by interactions with another mitochondrial protein, TUFM (Tu translation elongation factor, mitochondrial) (30).…”

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confidence: 99%

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NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

Qin

Xue

Liu

et al. 2017

J Virol

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Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. However, attenuation or termination of signaling is also necessary for preventing immune-mediated tissue damage and spontaneous autoimmunity. Here, we identify NLRX1 as a negative regulator for MAVS-mediated signaling pathway during HCV infection. Depletion of NLRX1 enhances HCV-triggered activation of IFN signaling and causes the suppression of HCV propagation in hepatocytes. NLRX1, a HCV-inducible protein, interacts with MAVS and mediates the K48-linked polyubiquitination and the subsequent degradation of MAVS via proteasomal pathway. Moreover, PCBP2 interacts with NLRX1 to participate in NLRX1-induced degradation of MAVS and inhibition of antiviral responses during HCV infection. Mutagenic analyses further revealed that the NOD domain of NLRX1 is essential for NLRX1 to interact with PCBP2 and subsequently induce MAVS degradation. Our study unlocks a key mechanism of fine tuning of innate immunity by which NLRX1 restrains RLRs-MAVS signaling cascade by recruiting PCBP2 to MAVS for inducing MAVS degradation through the proteasomal pathway. NLRX1, a negative regulator of innate immunity, is a pivotal host factor for HCV to establish persistent infection. Innate immunity needs to be tightly regulated to maximize antiviral response and minimize immune-mediated pathology. Whereas, the underlying mechanisms are poorly understood. In this study, we report that NLRX1 is a proviral host factor for HCV infection and functions as a negative regulator in HCV-triggered innate immune response. NLRX1 recruits PCBP2 to MAVS and induces the K48-linked polyubiquitination and degradation of MAVS, leading to the negative regulation of IFN signaling pathway and promoting HCV infection. Overall, this study provides intriguing insights into how innate immunity is regulated during viral infection.

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Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Xuan,

2023

ChemMedChem

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Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell‐mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long‐lasting anti‐tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

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NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses

Cited by 133 publications

References 47 publications

Inflammasomes and its importance in viral infections

Inflammasomes and its importance in viral infections

NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

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