CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.

<h4>Background</h4>The helminth Schistosoma mansoni parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear f...

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Autores principales:	Isabel Caetano de Abreu da Silva, Vitor Coutinho Carneiro, Renata de Moraes Maciel, Rodrigo Furtado Madeiro da Costa, Daniel Rodrigues Furtado, Francisco Meirelles Bastos de Oliveira, Mário Alberto Cardoso da Silva-Neto, Franklin David Rumjanek, Marcelo Rosado Fantappié
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/10f03772e47a4669b78e00770ee37b28
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spelling	oai:doaj.org-article:10f03772e47a4669b78e00770ee37b282021-11-18T06:47:23ZCK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.1932-620310.1371/journal.pone.0023572https://doaj.org/article/10f03772e47a4669b78e00770ee37b282011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21887276/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The helminth Schistosoma mansoni parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear factor, can also be secreted and act as a cytokine. Schistosome HMGB1 (SmHMGB1) is secreted by the eggs and stimulate the production of key cytokines involved in the pathology of schistosomiasis. Thus, understanding the mechanism of SmHMGB1 release becomes mandatory. Here, we addressed the question of how the nuclear SmHMGB1 can reach the extracellular space.<h4>Principal findings</h4>We showed in vitro and in vivo that CK2 phosphorylation was involved in the nucleocytoplasmic shuttling of SmHMGB1. By site-directed mutagenesis we mapped the two serine residues of SmHMGB1 that were phosphorylated by CK2. By DNA bending and supercoiling assays we showed that CK2 phosphorylation of SmHMGB1 had no effect in the DNA binding activities of the protein. We showed by electron microscopy, as well as by cell transfection and fluorescence microscopy that SmHMGB1 was present in the nucleus and cytoplasm of adult schistosomes and mammalian cells. In addition, we showed that treatments of the cells with either a phosphatase or a CK2 inhibitor were able to enhance or block, respectively, the cellular traffic of SmHMGB1. Importantly, we showed by confocal microscopy and biochemically that SmHMGB1 is significantly secreted by S. mansoni eggs of infected animals and that SmHMGB1 that were localized in the periovular schistosomotic granuloma were phosphorylated.<h4>Conclusions</h4>We showed that secretion of SmHMGB1 is regulated by phosphorylation. Moreover, our results suggest that egg-secreted SmHMGB1 may represent a new egg antigen. Therefore, the identification of drugs that specifically target phosphorylation of SmHMGB1 might block its secretion and interfere with the pathogenesis of schistosomiasis.Isabel Caetano de Abreu da SilvaVitor Coutinho CarneiroRenata de Moraes MacielRodrigo Furtado Madeiro da CostaDaniel Rodrigues FurtadoFrancisco Meirelles Bastos de OliveiraMário Alberto Cardoso da Silva-NetoFranklin David RumjanekMarcelo Rosado FantappiéPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23572 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Isabel Caetano de Abreu da Silva Vitor Coutinho Carneiro Renata de Moraes Maciel Rodrigo Furtado Madeiro da Costa Daniel Rodrigues Furtado Francisco Meirelles Bastos de Oliveira Mário Alberto Cardoso da Silva-Neto Franklin David Rumjanek Marcelo Rosado Fantappié CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
description	<h4>Background</h4>The helminth Schistosoma mansoni parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear factor, can also be secreted and act as a cytokine. Schistosome HMGB1 (SmHMGB1) is secreted by the eggs and stimulate the production of key cytokines involved in the pathology of schistosomiasis. Thus, understanding the mechanism of SmHMGB1 release becomes mandatory. Here, we addressed the question of how the nuclear SmHMGB1 can reach the extracellular space.<h4>Principal findings</h4>We showed in vitro and in vivo that CK2 phosphorylation was involved in the nucleocytoplasmic shuttling of SmHMGB1. By site-directed mutagenesis we mapped the two serine residues of SmHMGB1 that were phosphorylated by CK2. By DNA bending and supercoiling assays we showed that CK2 phosphorylation of SmHMGB1 had no effect in the DNA binding activities of the protein. We showed by electron microscopy, as well as by cell transfection and fluorescence microscopy that SmHMGB1 was present in the nucleus and cytoplasm of adult schistosomes and mammalian cells. In addition, we showed that treatments of the cells with either a phosphatase or a CK2 inhibitor were able to enhance or block, respectively, the cellular traffic of SmHMGB1. Importantly, we showed by confocal microscopy and biochemically that SmHMGB1 is significantly secreted by S. mansoni eggs of infected animals and that SmHMGB1 that were localized in the periovular schistosomotic granuloma were phosphorylated.<h4>Conclusions</h4>We showed that secretion of SmHMGB1 is regulated by phosphorylation. Moreover, our results suggest that egg-secreted SmHMGB1 may represent a new egg antigen. Therefore, the identification of drugs that specifically target phosphorylation of SmHMGB1 might block its secretion and interfere with the pathogenesis of schistosomiasis.
format	article
author	Isabel Caetano de Abreu da Silva Vitor Coutinho Carneiro Renata de Moraes Maciel Rodrigo Furtado Madeiro da Costa Daniel Rodrigues Furtado Francisco Meirelles Bastos de Oliveira Mário Alberto Cardoso da Silva-Neto Franklin David Rumjanek Marcelo Rosado Fantappié
author_facet	Isabel Caetano de Abreu da Silva Vitor Coutinho Carneiro Renata de Moraes Maciel Rodrigo Furtado Madeiro da Costa Daniel Rodrigues Furtado Francisco Meirelles Bastos de Oliveira Mário Alberto Cardoso da Silva-Neto Franklin David Rumjanek Marcelo Rosado Fantappié
author_sort	Isabel Caetano de Abreu da Silva
title	CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
title_short	CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
title_full	CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
title_fullStr	CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
title_full_unstemmed	CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.
title_sort	ck2 phosphorylation of schistosoma mansoni hmgb1 protein regulates its cellular traffic and secretion but not its dna transactions.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/10f03772e47a4669b78e00770ee37b28
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CK2 phosphorylation of Schistosoma mansoni HMGB1 protein regulates its cellular traffic and secretion but not its DNA transactions.

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