NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation

Tattoli, Ivan; Killackey, Samuel A.; Foerster, Elisabeth G.; Molinaro, Raphael; Maisonneuve, Charles; Rahman, Muhammed A.; Winer, Shawn; Winer, Daniel A.; Streutker, Catherine; Philpott, Dana J.; Girardin, Stephen E.

doi:10.1016/j.celrep.2016.02.065

Cited by 53 publications

(54 citation statements)

References 38 publications

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“…In addition to our current findings, prior studies have also evaluated NLRX1 in cancer utilizing either xenograft models or models of inflammation driven colorectal cancer [16, 17, 25, 26]. In the xenograft study, nude mice were injected with RKO colon carcinoma cells, where NLRX1 was either stably knocked down or overexpressed [16].…”

Section: Discussionmentioning

confidence: 78%

“…In the presence of TNF, NLRX1 knockdown resulted in significantly increased tumor volume, whereas overexpression attenuated tumor growth [16]. To evaluate the role of NLRX1 in CAC, tumorigenesis was induced in wild type and Nlrx1 −/− mice by treating the animals with the chemical carcinogen azoxymethane (AOM) immediately prior to dextran sulfate sodium (DSS) exposure [17, 25, 26]. In this model, inflammation associated with DSS exposure functions as a tumor promoter.…”

Section: Discussionmentioning

confidence: 99%

“…In this model, inflammation associated with DSS exposure functions as a tumor promoter. The results show that Nlrx1 −/− mice were significantly more sensitive to inflammation driven tumorigenesis compared to similarly treated wild type animals [17, 25, 26]. Significantly higher numbers and larger-sized polyps were observed in the Nlrx1 −/− mice [17].…”

Section: Discussionmentioning

confidence: 99%

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NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

et al. 2016

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Histiocytic sarcoma is an uncommon malignancy in both humans and veterinary species. Research exploring the pathogenesis of this disease is scarce; thus, diagnostic and therapeutic options for patients are limited. Recent publications have suggested a role for the NLR, NLRX1, in acting as a tumor suppressor. Based on these prior findings, we hypothesized that NLRX1 would function to inhibit tumorigenesis and thus the development of histiocytic sarcoma. To test this, we utilized Nlrx1−/− mice and a model of urethane-induced tumorigenesis. Nlrx1−/− mice exposed to urethane developed splenic histiocytic sarcoma that was associated with significant up-regulation of the NF-λB signaling pathway. Additionally, development of these tumors was also significantly associated with the increased regulation of genes associated with AKT signaling, cell death and autophagy. Together, these data show that NLRX1 suppresses tumorigenesis and reveals new genetic pathways involved in the pathobiology of histiocytic sarcoma.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

et al. 2016

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“…Previously, NLRX1 has been linked to the viral response, innate immunity and downstream effects on NF-κB signaling [4–7]. Located on the outer mitochondrial membrane, NLRX1 has been shown to influence reactive oxygen species production and the proliferation of epithelial cells in the context of colorectal cancer disease models [8–10]. As such, NLRX1 is a potential immunoregulatory molecule that integrates immune and metabolic function.…”

Section: Introductionmentioning

confidence: 99%

NLRX1 Regulates Effector and Metabolic Functions of CD4+ T Cells

Leber

Hontecillas

Tubau-Juni

et al. 2017

The Journal of Immunology

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Nucleotide oligomerization domain (NOD) like receptor X1 (NLRX1) has been implicated in viral response, cancer progression and inflammatory disorders; however, its role as a dual modulator of CD4+ T cell function and metabolism has not yet been defined. The loss of NLRX1 results in increased disease severity, populations of T helper 1 and T helper 17, and inflammatory markers (IFNγ, TNFα, and IL-17) in mice with DSS colitis. To further characterize this phenotype, we employed in vitro CD4+ T cell differentiation assays and show that NLRX1 deficient T cells have a greater ability to differentiate into inflammatory phenotype and greater proliferation rates. Further, NLRX1−/− cells have a decreased responsiveness to immune checkpoint pathways and greater rates of lactate dehydrogenase activity. When metabolic effects of the knockout are impaired, NLRX1 deficient cells do not display significant differences in differentiation or proliferation. To confirm the role of NLRX1 specifically in T cells, we used an adoptive transfer model of colitis. Rag2−/− recipient mice of NLRX1−/− naïve or effector T cells experienced increased disease activity and effector T cell populations, while no differences were observed between groups receiving wild-type or NLRX1−/− regulatory T cells. Metabolic effects of NLRX1 deficiency are observed in a CD4-specific knockout of NLRX1 within a C. rodentium model of colitis. The aerobic glycolytic preference in NLRX1−/− effector T cells is combined with a decreased sensitivity to immunosuppressive checkpoint pathways to provide greater proliferative capabilities and an inflammatory phenotype bias leading to increased disease severity.

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“…Furthermore, NLRX1 promotes virus-induced autophagy by interactions with another mitochondrial protein, TUFM (Tu translation elongation factor, mitochondrial) (30). Interestingly, two recent studies demonstrated that NLRX1 acts as a tumor suppressor to reduce tumorigenesis through regulating tumor necrosis factor (TNF) and IL-6 signaling pathways (31,32). However, the potential functions of NLRX1 in HCV propagation and the HCV-induced innate immune response remain unknown.…”

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confidence: 99%

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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NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation

Cited by 53 publications

References 38 publications

NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

NLRX1 Regulates Effector and Metabolic Functions of CD4+ T Cells

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

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