Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

Stack, Julianne; Hurst, Tara; Flannery, Sinead M.; Brennan, Kiva; Rupp, Sebastian; Oda, Shun-ichiro; Khan, Amir R.; Bowie, Andrew

doi:10.1074/jbc.m113.485490

Cited by 15 publications

(11 citation statements)

References 48 publications

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“…Next, to identify the kinases responsible for P62 induction, we focused on P38, which is a downstream kinase activated by TRAF64344. In the present study, we found that IR facilitated P38/P62 activation in livers leading to the accumulation of LC3II and autophagic vacuoles.…”

Section: Discussionmentioning

confidence: 55%

“…LPS-induced ALIS formation is dependent on P62 levels, and knockdown of either of these molecules (such as MyD88, IRAK4, TRAF6) decreases LPS-induced GFP-LC3 + dot formation 22 . Next, to identify the kinases responsible for P62 induction, we focused on P38, which is a downstream kinase activated by TRAF6 43 44 . In the present study, we found that IR facilitated P38/P62 activation in livers leading to the accumulation of LC3II and autophagic vacuoles.…”

Section: Discussionmentioning

confidence: 99%

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Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Wang

et al. 2017

Sci Rep

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Increasing evidence has linked autophagy to a detrimental role in hepatic ischemia- reperfusion (IR) injury (IRI). Here we focus on the role of interferon regulatory factor-1 (IRF-1) in regulating autophagy to aggravate hepatic IRI. We found that IRF-1 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling. This increased IRF-1 expression, which was allied with high autophagic activity, amplified liver damage to IR, an effect which was abrogated by IRF-1 depletion. Moreover, IRF-1 contributed to P38 induced autophagic and apoptotic cell death, that can play a key role in liver dysfunction. The levels of P62 mRNA and protein were increased when P38 was activated and decreased when P38 was inhibited by SB203580. We conclude that IRF-1 functioned as a trigger to activate autophagy via P38 activation and that P62 was required for this P38-mediated autophagy. IRF-1 appears to exert a pivotal role in hepatic IRI, by predisposing hepatocytes to activate an autophagic pathway. Such an effect promotes autophagic cell death through the P38/P62 pathway. The identification of this novel pathway, that links expression levels of IRF-1 with autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Wang

et al. 2017

Sci Rep

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“…The panels below each graph show that the expression levels of the different proteins were similar, except A49, which was expressed at much lower levels, especially in HeLa cells. Previously, it was reported that A46 inhibits Toll-like receptor/IL-1-stimulated MAPKs and NF-κB activation, whereas A52 can activate p38 MAPK and JNK activity, but whether these Bcl-2-like proteins can also induce AP-1 was not demonstrated ( Bowie et al , 2000 ; 2005 , Stack et al , 2013 ; Stack & Bowie, 2012 ; Maloney et al , 2005 ; Keating et al , 2007 ). B14 was also reported to increase PMA-stimulated AP-1 activity ( Chen et al , 2008 ).…”

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confidence: 99%

Multiple Bcl-2 family immunomodulators from vaccinia virus regulate MAPK/AP-1 activation

Torres

Albarnaz

Bonjardim

et al. 2016

Journal of General Virology

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Vaccinia virus (VACV) is a poxvirus and encodes many proteins that modify the host cell metabolism or inhibit the host response to infection. For instance, it is known that VACV infection can activate the mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) pathway and inhibit activation of the pro-inflammatory transcription factor NF-κB. Since NF-κB and MAPK/AP-1 share common upstream activators we investigated whether six different VACV Bcl-2-like NF-κB inhibitors can also influence MAPK/AP-1 activation. Data presented show that proteins A52, B14 and K7 each contribute to AP-1 activation during VACV infection, and when expressed individually outwith infection. B14 induced the greatest stimulation of AP-1 and further investigation showed B14 activated mainly the MAPKs ERK (extracellular signal-regulated kinase) and JNK (Jun N-terminal kinase), and their substrate c-Jun (a component of AP-1). These data indicate that the same viral protein can have different effects on distinct signalling pathways, in blocking NF-κB activation whilst leading to MAPK/AP-1 activation.

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“…For immunoblotting, a total of 30 mg of protein extract was separated on 10% SDS-PAGE gels and transferred to nitrocellulose membranes. For the dimerization studies, cell lysates were analyzed on native (nondenaturing) gels (13). The levels of protein expression were evaluated by Western blot as previously described in detail (14).…”

Section: Immunoblot Analysismentioning

confidence: 99%

Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis

et al. 2018

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Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75) and subsequent generation of the p75 intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75 ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75 ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75 ICD also promoted tumor metastasis formation Together, our findings uncover a previously unknown function for the ADAM10-p75 ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75 ICD as potential cancer therapeutic targets. These findings identify the ADAM10-p75 ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. .

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Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

Cited by 15 publications

References 48 publications

Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

Multiple Bcl-2 family immunomodulators from vaccinia virus regulate MAPK/AP-1 activation

Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis

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