FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.

The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and valid...

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Autores principales:	Yuji Kajiwara, Afia Akram, Pavel Katsel, Vahram Haroutunian, James Schmeidler, Gary Beecham, Jonathan L Haines, Margaret A Pericak-Vance, Joseph D Buxbaum
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46b9023f00914bcca4c317ff211da94c
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spelling	oai:doaj.org-article:46b9023f00914bcca4c317ff211da94c2021-11-25T06:16:18ZFE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.1932-620310.1371/journal.pone.0005071https://doaj.org/article/46b9023f00914bcca4c317ff211da94c2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19343227/?tool=EBIhttps://doaj.org/toc/1932-6203The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome.Yuji KajiwaraAfia AkramPavel KatselVahram HaroutunianJames SchmeidlerGary BeechamJonathan L HainesMargaret A Pericak-VanceJoseph D BuxbaumPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 4, p e5071 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuji Kajiwara Afia Akram Pavel Katsel Vahram Haroutunian James Schmeidler Gary Beecham Jonathan L Haines Margaret A Pericak-Vance Joseph D Buxbaum FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
description	The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome.
format	article
author	Yuji Kajiwara Afia Akram Pavel Katsel Vahram Haroutunian James Schmeidler Gary Beecham Jonathan L Haines Margaret A Pericak-Vance Joseph D Buxbaum
author_facet	Yuji Kajiwara Afia Akram Pavel Katsel Vahram Haroutunian James Schmeidler Gary Beecham Jonathan L Haines Margaret A Pericak-Vance Joseph D Buxbaum
author_sort	Yuji Kajiwara
title	FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
title_short	FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
title_full	FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
title_fullStr	FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
title_full_unstemmed	FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.
title_sort	fe65 binds teashirt, inhibiting expression of the primate-specific caspase-4.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/46b9023f00914bcca4c317ff211da94c
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FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.

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