NF-κB activation and polyubiquitin conjugation are required for pulmonary inflammation-induced diaphragm atrophy

Haegens, Astrid; Schols, A.M.W.J.; Gorissen, Stefan H.M.; Essen, Anon Lm; Snepvangers, Frank J. M.; Gray, Douglas A.; Shoelson, Steven E.; Langen, Ramon

doi:10.1152/ajplung.00084.2011

Cited by 38 publications

(35 citation statements)

References 35 publications

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“…Interestingly, the fact that NF-B activation is totally blocked by using a specific muscle inhibitor demonstrates that NF-B activation by LPS occurs mainly in muscle cells and not in immune cells localized in the muscle. In contrast to our results, recent reports have shown that NF-B activation is required to induce MuRF1 expression and diaphragm muscle atrophy in acute pulmonary inflammation (12,20,30). The discrepancy between the present work and these studies could be easily explained by a crucial difference in the experimental design.…”

Section: Discussioncontrasting

confidence: 99%

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Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

Schakman

Dehoux

Bouchuari

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.

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Section: Discussioncontrasting

confidence: 99%

“…In addition, sepsis is associated with activation of NF-B in skeletal muscle (43). Finally, inhibition of NF-B prevents proteolysis in TNF␣/interferon-␥ (IFN␥)-treated myotubes (28) and muscle atrophy caused by denervation, disuse (i.e., hindlimb unloading) (3,59) and pulmonary inflammation (20).…”

mentioning

confidence: 99%

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

Schakman

Dehoux

Bouchuari

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Transgenic mice specifically overexpressing NF-κB in muscle show muscle atrophy due to UPS-mediated protein degradation, resulting from the overexpression of a muscle-specific E3 ligase, MuRF1 [44]. In addition, the induction of MuRF1 in diaphragm muscle during inflammation by NF-κB was shown using transgenic mice in which “muscle IκBα super repressor” (MISR) signaling is repressed in the muscle [45]. These previous reports support the possibility that NF-κB induced UPS-mediated protein degradation in the inflamed retina, although further studies are required.…”

Section: Discussionmentioning

confidence: 99%

AMPK-NF-κB Axis in the Photoreceptor Disorder during Retinal Inflammation

et al. 2014

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Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the retinal neural damage and visual function impairment caused by inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during retinal inflammation.

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“…The structures of PTPN18-HER2-pY 1248 , pY 1112 and pY 1196 were determined by molecular replacement with Phaser 55 in the CCP4 software package. A single chain of the PTPN18 catalytic domain (PDB code: 2OC3, water deleted) was used as the initial search model 56,57 . Further refinements were carried out using the PHENIX program with iterative manual building in COOT 57 .…”

Section: Methodsmentioning

confidence: 99%

“…A single chain of the PTPN18 catalytic domain (PDB code: 2OC3, water deleted) was used as the initial search model 56,57 . Further refinements were carried out using the PHENIX program with iterative manual building in COOT 57 . Composite omitted maps were built, and density modification was carried out to reduce the phase biases during further refinement.…”

Section: Methodsmentioning

confidence: 99%

The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes

Wang

Ning

et al. 2014

Cell Res

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The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. Here, we demonstrate that PTPN18 regulates HER2-mediated cellular functions through defining both its phosphorylation and ubiquitination barcodes. Enzymologic characterization and three crystal structures of PTPN18 in complex with HER2 phospho-peptides revealed the molecular basis for the recognition between PTPN18 and specific HER2 phosphorylation sites, which assumes two distinct conformations. Unique structural properties of PTPN18 contribute to the regulation of sub-cellular phosphorylation networks downstream of HER2, which are required for inhibition of HER2-mediated cell growth and migration. Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY1112, the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. In agreement with the negative regulatory role of PTPN18 in HER2 signaling, the HER2/PTPN18 ratio was correlated with breast cancer stage. Taken together, our study presents a structural basis for selective HER2 dephosphorylation, a previously uncharacterized mechanism for HER2 degradation and a novel function for the PTPN18 PEST domain. The new regulatory role of the PEST domain in the ubiquitination pathway will broaden our understanding of the functions of other important PEST domain-containing phosphatases, such as LYP and PTPN12.

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NF-κB activation and polyubiquitin conjugation are required for pulmonary inflammation-induced diaphragm atrophy

Cited by 38 publications

References 35 publications

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

AMPK-NF-κB Axis in the Photoreceptor Disorder during Retinal Inflammation

The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes

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