The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1

Killackey, Samuel A.; Rahman, Muhammed A.; Soares, Fraser; Zhang, Ashley B.; Abdel-Nour, Mena; Philpott, Dana J.; Girardin, Stephen E.

doi:10.1007/s11010-018-3444-3

Cited by 35 publications

(24 citation statements)

References 34 publications

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“…This attenuation of NLRX1 and subsequent elimination in mitochondrial ROS production was associated with improved cell survival, tight junction formation, and barrier function (43). Contrastingly, NLRX1 reportedly exerts protective effects against apoptosis in chondrocytes and tubular epithelial cells, and the modulation of apoptosis may be dependent on its interactions with yet another protein, SARM1 (37, 41, 75).…”

Section: Nlrx1 Regulates Immune System Function Through Mitochondria mentioning

confidence: 95%

NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function

2019

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Over the last decade, significant progress has been achieved in defining mechanisms underlying NLR regulation of immune system function. However, several NLR family members continue to defy our best attempts at characterization and routinely exhibit confounding data. This is particularly true for NLR family members that regulate signaling associated with the activation of other pattern recognition receptors. NLRX1 is a member of this NLR sub-group and acts as an enigmatic regulator of immune system function. NLRX1 has been shown to negatively regulate type-I interferon, attenuate pro-inflammatory NF-κB signaling, promote reactive oxygen species production, and modulate autophagy, cell death, and proliferation. However, the mechanism/s associated with NLRX1 modulation of these pathways is not fully understood and there are inconsistencies within the field. Likewise, it is highly likely that the full repertoire of biological functions impacted by NLRX1 are yet to be defined. Recent mouse studies have shown that NLRX1 significantly impacts a multitude of diseases, including cancer, virus infection, osteoarthritis, traumatic brain injury, and inflammatory bowel disease. Thus, it is essential that the underlying mechanism associated with NLRX1 function in each of these diseases be robustly defined. Here, we summarize the current progress in understanding mechanisms associated with NLRX1 function. We also offer insight into both unique and overlapping mechanisms regulated by NLRX1 that likely contribute to disease pathobiology. Ultimately, we believe that an improved understanding of NLRX1 will result in better defined mechanisms associated with immune system attenuation and the resolution of inflammation in a myriad of diseases.

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Section: Nlrx1 Regulates Immune System Function Through Mitochondria mentioning

confidence: 95%

NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function

2019

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“…Lentiviral knockdown of HRI expression was performed as previously described (11) and HRI -/cell line generation and characterization was also previously described (11). Stimulation with TNF (10ng/ml, Cell Signaling technology) plus cycloheximide (10µg/ml) was performed similar to previously (49). MG132 and chloroquine were from Sigma.…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Mukherjee

Ramaglia

Abdel-Nour

et al. 2021

Journal of Biological Chemistry

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Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response (cUPR) to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

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“…Thus, NLRX1 may produce effects partly through inflammation and apoptosis pathways. NLRX1 has also been shown to regulate apoptosis via sterile alpha and Toll/interleukin-1 receptor motif containing protein 1 [ 12 ]. Moreover, a recent study showed that NLRX1 mediates mitophagy through its LC3-interacting region motif binding to LC3 in cells induced by bacterial pathogens [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-423-5P Regulates Cells Apoptosis and Extracellular Matrix Degradation via Nucleotide-Binding, Leucine-Rich Repeat Containing X1 (NLRX1) in Interleukin 1 beta (IL-1β)-Induced Human Nucleus Pulposus Cells

et al. 2020

Med Sci Monit

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Background Disc degeneration is characterized partly by the degradation in the extracellular matrix (ECM) and excess apoptosis of nucleus pulposus (NP) cells. NLRX1 (nucleotide-binding, leucine-rich repeat containing X1) is different from the other nucleotide-binding-domain and leucine-rich-repeat proteins and mainly located to the mitochondrial. It negatively regulates NF-κB (nuclear factor kappa B) and apoptosis inhibition. However, how NLRX1 is regulated and exerts effects in disc degeneration is unclear. Thus, the study aimed to analyze the effects of NLRX1 on NP cells. Material/Methods NLRX1 expression was detected in interleukin (IL)-1β-induced NP cells by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Then, NLRX1 was overexpressed in IL-1β-induced NP cells to detect apoptosis-related proteins and the extracellular matrix (ECM) by western blot, along with the detection of apoptosis levels using flow cytometry. StarBase predicted miR-423-5p target 3′UTR of NLRX1. Dual luciferase reporter assay showed that miR-423-5p could bind to the 3′UTR of NLRX1. Besides, miR-423-5p significantly affected NLRX1 levels detected by qRT-qPCR. Results The miR-423-5p overexpression markedly, and negatively regulated the protective effects of NLRX1 on IL-1β induced NP cells. Thus, our results suggested that miR-423-5p mediated the regulation of NLRX1 to affect apoptosis and ECM levels in IL-1β induced NP cells. Conclusions miR-423-5p and NLRX1 could be potential therapeutic targets for patients with disc degeneration.

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The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1

Cited by 35 publications

References 34 publications

NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function

NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

MiR-423-5P Regulates Cells Apoptosis and Extracellular Matrix Degradation via Nucleotide-Binding, Leucine-Rich Repeat Containing X1 (NLRX1) in Interleukin 1 beta (IL-1β)-Induced Human Nucleus Pulposus Cells

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