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MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)

There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption...

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Autores principales: Yuan, Huijuan, Sehgal, Pravin B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119740/
https://www.ncbi.nlm.nih.gov/pubmed/27875556
http://dx.doi.org/10.1371/journal.pone.0166382
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author Yuan, Huijuan
Sehgal, Pravin B.
author_facet Yuan, Huijuan
Sehgal, Pravin B.
author_sort Yuan, Huijuan
collection PubMed
description There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2. In human pulmonary arterial endothelial cells (HPAECs), IFN-α-induced endogenous as well as exogenously expressed MxA was associated with endosomes that aligned alongside microtubules and tubules of the endoplasmic reticulum (ER). Moreover, IFN-α and MxA stimulated basal and BMP4/9 signaling to a Smad1/5/8-responsive pBRE-Luc reporter. In HEK293T cells, immunoelectron microscopy confirmed the association of MxA with endosomes, and immunofluorescence methods showed these to be positive for early endosome markers (early endosomal antigen 1, clathrin light chain and Rab5) and RSmad1/5/8. Functionally, using different genetic and inhibitor approaches, we observed that clathrin-mediated endocytosis enhanced and caveolin-mediated endocytosis inhibited the transcriptional response to BMP4 and BMP9. MxA produced a further 3-4-fold enhancement of the BMP-induced response in a clathrin-endocytosis dependent manner. The microtubule inhibitor nocodazole and stabilizer paclitaxel respectively attenuated and enhanced the effect of MxA, implicating microtubule integrity in this process. MxA enhanced BMP-induced signaling in the presence of wild-type BMPR2, and partially rescued signaling from some PAH-disease-associated BMPR2 mutants. Taken together, the data identify MxA as a novel stimulator of BMP4 and BMP9 transcriptional signaling, and suggest it to be a candidate IFN-α-inducible mechanism that might have a protective role against development of PAH and other vascular diseases.
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spelling pubmed-51197402016-12-15 MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9) Yuan, Huijuan Sehgal, Pravin B. PLoS One Research Article There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2. In human pulmonary arterial endothelial cells (HPAECs), IFN-α-induced endogenous as well as exogenously expressed MxA was associated with endosomes that aligned alongside microtubules and tubules of the endoplasmic reticulum (ER). Moreover, IFN-α and MxA stimulated basal and BMP4/9 signaling to a Smad1/5/8-responsive pBRE-Luc reporter. In HEK293T cells, immunoelectron microscopy confirmed the association of MxA with endosomes, and immunofluorescence methods showed these to be positive for early endosome markers (early endosomal antigen 1, clathrin light chain and Rab5) and RSmad1/5/8. Functionally, using different genetic and inhibitor approaches, we observed that clathrin-mediated endocytosis enhanced and caveolin-mediated endocytosis inhibited the transcriptional response to BMP4 and BMP9. MxA produced a further 3-4-fold enhancement of the BMP-induced response in a clathrin-endocytosis dependent manner. The microtubule inhibitor nocodazole and stabilizer paclitaxel respectively attenuated and enhanced the effect of MxA, implicating microtubule integrity in this process. MxA enhanced BMP-induced signaling in the presence of wild-type BMPR2, and partially rescued signaling from some PAH-disease-associated BMPR2 mutants. Taken together, the data identify MxA as a novel stimulator of BMP4 and BMP9 transcriptional signaling, and suggest it to be a candidate IFN-α-inducible mechanism that might have a protective role against development of PAH and other vascular diseases. Public Library of Science 2016-11-22 /pmc/articles/PMC5119740/ /pubmed/27875556 http://dx.doi.org/10.1371/journal.pone.0166382 Text en © 2016 Yuan, Sehgal http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yuan, Huijuan
Sehgal, Pravin B.
MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title_full MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title_fullStr MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title_full_unstemmed MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title_short MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)
title_sort mxa is a novel regulator of endosome-associated transcriptional signaling by bone morphogenetic proteins 4 and 9 (bmp4 and bmp9)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119740/
https://www.ncbi.nlm.nih.gov/pubmed/27875556
http://dx.doi.org/10.1371/journal.pone.0166382
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