Expression of cFLIPL Determines the Basal Interaction of Bcl‐2 With Beclin‐1 and Regulates p53 Dependent Ubiquitination of Beclin‐1 During Autophagic Stress

Ranjan, Kishu; Pathak, Chandramani

doi:10.1002/jcb.25474

Cited by 21 publications

(12 citation statements)

References 54 publications

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“…MiRNAs act through downregulating multiple target genes, while Beclin-1 is known as a key initiator of the autophagic process 27. The authors reported that miR-384 could modulate autophagy to anti-atherosclerosis by inhibiting Beclin-1 expression 28.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-384-5p/Beclin-1 As Potential Indicators For Epigallocatechin Gallate Against Cardiomyocytes Ischemia Reperfusion Injury By Inhibiting Autophagy Via PI3K/Akt Pathway

Zhang¹,

Liang²,

Gan³

et al. 2019

DDDT

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Background/Aims: Epigallocatechin gallate (EGCG) has established protective actions against myocardial ischemia/reperfusion (I/R) injury by regulating autophagy. However, little is known about the mechanisms of EGCG in posttranscriptional regulation in the process of cardioprotection. Here we studied whether microRNAs play a role in EGCG-induced cardioprotection. Methods: The myocardial I/R injury in vitro and in vivo model were made, with or without EGCG pretreatment. The upregulation and silencing of microRNA-384-5p (miR-384) and Beclin-1 in H9c2 cell lines were established. Rats were transfected with miR-384 specific shRNA. Dual-luciferase reporter gene assay was conducted to verify the relationship between miR-384 and Beclin-1. TTC staining was performed to analyze the area of myocardial infarct size. Cell viability was monitored by cell counting kit-8 (CCK-8). The release of cardiac troponin-I (cTnI) was examined by ELISA. The levels of autophagy-related genes or proteins expression were evaluated by qRT-PCR or Western blotting. Autophagosomes of myocardial cells were detected by transmission electron microscopy and laser scanning confocal microscope. Results: I/R increased both autophagosomes and autolysosomes, thereby increasing autophagic flux both in vitro and in vivo. Pretreatment with EGCG attenuated I/R-induced autophagic flux expression, accompanied by an increase in cell viability and a decrease in the size of myocardial infarction. MiR-384 expression was down-regulated in H9c2 cell lines when subjected to I/R, while this suppression could be reversed by EGCG pretreatment. The dual-luciferase assay verified that Beclin-1 was a target of miR-384. Both overexpression of miR-384 and knocking down of Beclin-1 significantly inhibited I/R-induced autophagy, accompanied by the activation of PI3K/Akt pathway, thus enhanced the protective effect of EGCG. However, these functions were abrogated by the PI3K inhibitor, LY294002. Conclusion: We confirmed that EGCG has a protective role in microRNA-384-mediated autophagy by targeting Beclin-1 via activating the PI3K/Akt signaling pathway. Our results unveiled a novel role of EGCG in myocardial protection, involving posttranscriptional regulation with miRNA-384.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-384-5p/Beclin-1 As Potential Indicators For Epigallocatechin Gallate Against Cardiomyocytes Ischemia Reperfusion Injury By Inhibiting Autophagy Via PI3K/Akt Pathway

Zhang¹,

Liang²,

Gan³

et al. 2019

DDDT

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“…However, in the presence of FADD, stimulation of TNF-α significantly enhances ROS level and ubiquitination of cFLIP L in HEK 293T cells. Moreover, knockdown of the cFLIP L has been reported to augment ROS generation and JNK activation in tumor cells 28 62 . We demonstrate here that knockdown of cFLIP L in TNF-α primed cells progressively enhance the ROS accumulation and JNK1 activation, but this effect was counterbalanced in NAC pre-treated cells.…”

Section: Discussionmentioning

confidence: 99%

FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis

Ranjan

Pathak

2016

Sci Rep

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Tumor Necrosis Factor-α canonically induces the activation of NF-κB and associated gene product cellular FLICE-like inhibitory protein (cFLIP L ) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIP L and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-κB signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIP L and inhibition of NF-κB activation, independent of TNF-α stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIP L to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIP L that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.Fas associated death domain (FADD) is a pivotal signaling component of death receptor (DR) mediated apoptosis. DRs such as Fas (CD95/Apo) and tumor necrosis factor receptor 1 (TNFR1) (p55/CD120a), belongs to the TNF receptor super family that contain cytoplasmic death domain (DD) to execute downstream signal transduction 1 . Upon binding of ligand to the cell surface receptors, the DD of cell surface receptor homophilically interacts with the DD of FADD and induces oligomerization of DED (death effector domain) of FADD with apical caspases such as, procaspase 8/10 to form a death-inducing signaling complex (DISC) 2 . In the downstream, DISC facilitates processing and catalytic activation of caspases-8/10 to transduces downstream signaling of apoptosis 3 . However, the catalytic activation of caspase-8/10 has been negatively regulated by the anti-apoptotic protein Cellular Flice like inhibitory protein (cFLIP) to abrogate apoptotic instigation 4 . Although FADD is a multifunctional protein and its Fas ligand mediated proapoptotic function has been well studied 5,6 . However, the cellular dynamics of FADD and cFLIP in the regulation of cell death and survival by TNFR signaling remains elusive. TNF receptor (TNFR) signaling elicits both non-apoptotic and apoptotic response by the formation of two sequential complexes depending upon the stimulation of the TNF-α . The components of complex I constituted with TRADD, TRAF2, cIAPs and RIP1 activates NF-κ B signaling for promoting cell survival. However, the subsequent dissociation of RIP1 from complex I and association with FADD and procaspase-8 initiates formation of pro-apoptotic complex II that...

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“…Cytoplasmic HMGB1 is able to bind directly to beclin1, an important autophagy initiator, allowing it to form autophagy initiation complexes, which can remove harmful oxidative stresses (e.g., from mitochondria) . HMGB1 is able to bind beclin1 by displacing Bcl2, an apoptosis inhibitor, which once dissociated from beclin1 can perform its role in preventing programmed apoptotic cell death . Binding of HMGB1 to beclin1 occurs in the area of C23 and C45 and mutation of these cysteines to prevent disulfide bridge formation also prevents beclin1 association and diminishes autophagy (Fig.…”

Section: Redox Regulation Of Hmgb1 Functionmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

124

101

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High mobility group box 1 (HMGB1) is a multifunctional nuclear protein, probably known best as a prototypical alarmin or damage-associated molecular pattern (DAMP) molecule when released from cells. However, HMGB1 has multiple functions that depend on its location in the nucleus, in the cytosol, or extracellularly after either active release from cells, or passive release upon lytic cell death. Movement of HMGB1 between cellular compartments is a dynamic process induced by a variety of cell stresses and disease processes, including sepsis, trauma, and hemorrhagic shock.Location of HMGB1 is intricately linked with its function and is regulated by a series of posttranslational modifications. HMGB1 function is also regulated by the redox status of critical cysteine residues within the protein, and is cell-type dependent. This review highlights some of the mechanisms that contribute to location and functions of HMGB1, and focuses on some recent insights on important intracellular effects of HMGB1 during sepsis and trauma. K E Y W O R D S AIM2, autophagy, caspase-11, DAMPs, pyroptosis 2 NUCLEAR-TO-CYTOPLASM SHUTTLING OF HMGB1 HMGB1 consists of 215 aa residues, and contains 2 HMG DNAbinding domains, designated as A and B boxes, together with a negatively charged C-terminal acidic region. 14 Two nuclear localization sites (NLSs), one located in the A box (aa 28-44) and one in the B box (aa 179-185), control the nuclear localization of HMGB1 under homeostatic states. 14 Posttranslational modifications of NLS sites, including acetylation, phosphorylation, and methylation, regulate the ability of HMGB1 to translocate to the cytoplasm during cellular stress.Once in the cytoplasm HMGB1 can affect multiple inflammatory responses, and can be actively released into the extracellular space and circulation.

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Expression of cFLIP_L Determines the Basal Interaction of Bcl‐2 With Beclin‐1 and Regulates p53 Dependent Ubiquitination of Beclin‐1 During Autophagic Stress

Cited by 21 publications

References 54 publications

<p>MicroRNA-384-5p/Beclin-1 As Potential Indicators For Epigallocatechin Gallate Against Cardiomyocytes Ischemia Reperfusion Injury By Inhibiting Autophagy Via PI3K/Akt Pathway</p>

<p>MicroRNA-384-5p/Beclin-1 As Potential Indicators For Epigallocatechin Gallate Against Cardiomyocytes Ischemia Reperfusion Injury By Inhibiting Autophagy Via PI3K/Akt Pathway</p>

FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

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