Nur77 promotes cigarette smoke‑induced autophagic cell death by increasing the dissociation of Bcl2 from Beclin-1

Qin, Hong; Gao, Feng; Wang, Yanni; Huang, Bin; Peng, Ling; Mo, Biwen; Wang, Changming

doi:10.3892/ijmm.2019.4184

Cited by 12 publications

(12 citation statements)

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“…Contrasting with our findings, Qin et al reported that CS and CSE increased, rather than suppressed, Nur77 in lungs of mice or HBE cells and enhanced Nur77 nuclear export with a concurrent increase in autophagy of the cells [37]. Resolving this discrepancy will require further study, but we speculate that it is attributable to time-dependent differences in CS-induced alteration of Nur77 expression.…”

Section: Discussioncontrasting

confidence: 99%

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD)

et al. 2020

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Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-κB signaling pathway. Because it is unknown if Nur77's anti-inflammatory role modulates COPD, we assessed if and how Nur77 expression and activity are altered in CS-induced airway inflammation. In lung tissues and bronchial epithelial cells from COPD patients, we found Nur77 was downregulated. In a murine model of CS-induced airway inflammation, CS promoted lung inflammation and also reduced Nur77 activity in wild type (WT) mice, whereas lungs of Nur77-deficient mice showed exaggerated CS-induced inflammatory responses. Our findings in in vitro studies of human airway epithelial cells complemented those in vivo data in mice, together showing that CS induced threonine-phosphorylation of Nur77, which is known to interfere with its anti-inflammatory functions. In summary, our findings point to Nur77 as an important regulator of CS-induced inflammatory responses and support the potential benefits of Nur77 activation for COPD treatment.

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Section: Discussioncontrasting

confidence: 99%

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD)

et al. 2020

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“…Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo [15,16], displaying anticancer and chemopreventive properties in mice [17]. Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death [18], which seems to be mediated by releasing BECN1 in a model of cigarette smokeinduced autophagic cell death [19]. Taken together, these findings indicate that NR4A1 could function as a broad inducer of autophagic cell death.…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

et al. 2020

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NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and posttranslational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.

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“…Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo (15, 16), displaying anticancer and chemopreventive properties in mice(17). Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death (18), which seems to be mediated by releasing BECN1 in a model of cigarette smoke-induced autophagic cell death(19). Taken together, these findings indicate that NR4A1 could function as a broad inducer of autophagic cell death.…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

Castro-Obregón

Zárraga

Muciño-Hernández

et al. 2019

Preprint

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242 25 Abstract 26 NR4A is a nuclear receptor protein family whose members act as sensors of cellular 27 environment and regulate multiple processes such as metabolism, proliferation, migration, 28 apoptosis, and autophagy. Since the ligand binding domains of these receptors have no 29 cavity for ligand interaction, their function is most likely regulated by protein abundance 30 and post-translational modifications. In particular, NR4A1 is regulated by protein 31 abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic 32 translocation), and acts both as a transcription factor and as a regulator of other 33 interacting proteins. SUMOylation is a post-translational modification that can affect protein 34 stability, transcriptional activity, alter protein-protein interactions and modify intracellular 35 localization of target proteins. In the present study we evaluated the role of SUMOylation 36 as a posttranslational modification that can regulate the activity of NR4A1 to induce 37 autophagy-dependent cell death. We focused on a model potentially relevant for neuronal 38 cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic 39 cell death. We observed that a triple mutant in SUMOylation sites has reduced 40 SUMOylation, increased transcriptional activity, altered intracellular distribution, and more 41 importantly, its ability to induce autophagic cell death is impaired. 42 43 Summary Statement 44 The modification of the nuclear receptor NR4A1 by SUMO regulates its transcriptional 45 activity, intracellular localization and is required to induce autophagic cell death.46 47 Short title: SUMOylated NR4A1 induces autosis 48 49 Keywords: 50 NR4A1, SUMO, autophagy, cell death, Substance P, NK 1 R3 51 52 Abbreviations list 53 NR4A Nuclear receptor group family A 54 NR4A1 Nuclear receptor group 4 family A member 1 (Nur77, NGF1B, TR3, etc.) 55 NR4A2 Nuclear receptor group 4 family A member 2 (Nurr1, NOT1, etc) 56 NR4A3 Nuclear receptor group 4 family A member 3 (Nor1, MINOR) 57 SUMO small ubiquitin-like modifier 58 SP Substance P 59 NK 1 R Neurokinin 1 Receptor 60 TAD Trans-Activation Domain 61 DBD DNA Binding Domain 62 LBD Ligand Binding Domain 63 PTM Post Translational Modifications 4 64 Introduction 65 Nuclear receptors are a superfamily of transcription factors involved in a vast number of 66 biological processes. They share three common structural domains: a N-terminal 67 transactivation domain (TAD), a central double zinc finger DNA binding domain (DBD) and 68 a C-terminal ligand binding domain (LBD). Among the known human nuclear receptors, 69 the ones belonging to the NR4A family act as sensors of the cellular environment and 70 contribute to cell fate decisions, such as cell proliferation, differentiation, migration, cell 71 death, etc. Physiologically, NR4A members influence the adaptive and innate immune 72 system, angiogenesis, metabolism and brain function. The NR4A family is comprised of 73 three members that bind the same DNA elements (1): NR4A1 (Nur77, TR3, ...

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Nur77 promotes cigarette smoke‑induced autophagic cell death by increasing the dissociation of Bcl2 from Beclin-1

Cited by 12 publications

References 46 publications

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD)

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD)

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

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