The Mitochondrial Protein NLRX1 Controls the Balance between Extrinsic and Intrinsic Apoptosis

Soares, Fraser; Tattoli, Ivan; Rahman, Muhammed A.; Robertson, Susan J.; Belcheva, A.; Liu, Daniel; Streutker, Catherine; Winer, Shawn; Winer, Daniel A.; Martín, Alberto; Philpott, Dana J.; Arnoult, Damien; Girardin, Stephen E.

doi:10.1074/jbc.m114.550111

Cited by 65 publications

(62 citation statements)

References 19 publications

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“…Recently, our lab has identified a role for NLRX1 in the control of apoptotic cell death sensitivity in transformed but not primary cells, suggesting a link between NLRX1 and tumorigenesis (259). In addition, our data reveal that NLRX1-deficient mice exhibit resistance to colorectal cancer in an AOM model but increased susceptibility to AOM/ DSS-induced carcinogenesis, which was associated with increased apoptosis induced by DSS.…”

Section: Cancersupporting

confidence: 51%

NOD-Like Receptors: Versatile Cytosolic Sentinels

Motta

Soares

Sun

et al. 2015

Physiological Reviews

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267

206

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Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases.

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Section: Cancersupporting

confidence: 51%

NOD-Like Receptors: Versatile Cytosolic Sentinels

Motta

Soares

Sun

et al. 2015

Physiological Reviews

Self Cite

267

206

View full text Add to dashboard Cite

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“…NLRX1 has been previously shown to negatively regulate NF-κB signaling and this attenuation is correlated with increased proliferation and tumorigenesis in cancer models (11, 29). Thus, we next profiled gene expression to evaluate NF-κB signaling following TBI in the Nlrx1 −/− and wild type brain following CCI injury.…”

Section: Resultsmentioning

confidence: 99%

“…These findings support the previous observations with rotenone and provide additional mechanistic insight into the in vivo loss of neurons observed in the Nlrx1 −/− mice following TBI. Several prior studies have evaluated the role of NLRX1 in cell death and proliferation in monocytes, fibroblasts, and epithelial cells (11, 19, 29, 63). Likewise, NLRX1 has also been shown to modulate ROS signaling and autophagy in these diverse cells following activation via pathogen associated molecular pattern stimulation and/or pathogen exposure (14, 16, 29, 64, 65).…”

Section: Discussionmentioning

confidence: 99%

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Theus

Brickler

Meza

et al. 2017

The Journal of Immunology

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Traumatic and non-traumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity and free radical release contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we utilized Nlrx1−/− mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). Here, we show that the Nlrx1−/− mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-κB signaling cascade is significantly up-regulated in the Nlrx1−/− animals. This up-regulation is associated with increased microglia and macrophage populations in the cortical lesion. Utilizing a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-κB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

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“…A recent pair of studies have suggested that NLRX1 functions as a tumor suppressor through modulating apoptosis [16, 17]. In one study, NLRX1 expression was found to differentially regulate resistance to extrinsic and intrinsic apoptotic signals in transformed, but not primary murine embryonic fibroblasts [17]. In the other study, NLRX1 was found to function as a tumor suppressor by regulating TNF induced apoptosis in immortalized cell lines [16].…”

Section: Resultsmentioning

confidence: 99%

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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The Mitochondrial Protein NLRX1 Controls the Balance between Extrinsic and Intrinsic Apoptosis

Cited by 65 publications

References 19 publications

NOD-Like Receptors: Versatile Cytosolic Sentinels

NOD-Like Receptors: Versatile Cytosolic Sentinels

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

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

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