Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.

Autoimmune destruction of insulin producing pancreatic β-cells is the hallmark of type I diabetes. One of the key molecules implicated in the disease onset is the immunoproteasome, a protease with multiple proteolytic sites that collaborates with the constitutive 19S and the inducible 11S (PA28) act...

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Autores principales:	Wieke Freudenburg, Madhav Gautam, Pradipta Chakraborty, Jared James, Jennifer Richards, Alison S Salvatori, Aaron Baldwin, Jill Schriewer, R Mark L Buller, John A Corbett, Dorota Skowyra
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ce511bb44e184cc4a11634b4d99f5488
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spelling	oai:doaj.org-article:ce511bb44e184cc4a11634b4d99f54882021-11-18T07:59:02ZReduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.1932-620310.1371/journal.pone.0052408https://doaj.org/article/ce511bb44e184cc4a11634b4d99f54882013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23383295/?tool=EBIhttps://doaj.org/toc/1932-6203Autoimmune destruction of insulin producing pancreatic β-cells is the hallmark of type I diabetes. One of the key molecules implicated in the disease onset is the immunoproteasome, a protease with multiple proteolytic sites that collaborates with the constitutive 19S and the inducible 11S (PA28) activators to produce immunogenic peptides for presentation by MHC class I molecules. Despite its importance, little is known about the function and regulation of the immunoproteasome in pancreatic β-cells. Of special interest to immunoproteasome activation in β-cells are the effects of IFNβ, a type I IFN secreted by virus-infected cells and implicated in type I diabetes onset, compared to IFNγ, the classic immunoproteasome inducer secreted by cells of the immune system. By qPCR analysis, we show that mouse insulinoma MIN6 cells and mouse islets accumulate the immune proteolytic β1(i), β2(i) and β5(i), and 11S mRNAs upon exposure to IFNβ or IFNγ. Higher concentrations of IFNβ than IFNγ are needed for similar expression, but in each case the expression is transient, with maximal mRNA accumulation in 12 hours, and depends primarily on Interferon Regulatory Factor 1. IFNs do not alter expression of regular proteasome genes, and in the time frame of IFNβ-mediated response, the immune and regular proteolytic subunits co-exist in the 20S particles. In cell extracts with ATP, these particles have normal peptidase activities and degrade polyubiquitinated proteins with rates typical of the regular proteasome, implicating normal regulation by the 19S activator. However, ATP depletion rapidly stimulates the catalytic rates in a manner consistent with levels of the 11S activator. These findings suggest that stochastic combination of regular and immune proteolytic subunits may increase the probability with which unique immunogenic peptides are produced in pancreatic β-cells exposed to IFNβ, but primarily in cells with reduced ATP levels that stimulate the 11S participation in immunoproteasome function.Wieke FreudenburgMadhav GautamPradipta ChakrabortyJared JamesJennifer RichardsAlison S SalvatoriAaron BaldwinJill SchriewerR Mark L BullerJohn A CorbettDorota SkowyraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e52408 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wieke Freudenburg Madhav Gautam Pradipta Chakraborty Jared James Jennifer Richards Alison S Salvatori Aaron Baldwin Jill Schriewer R Mark L Buller John A Corbett Dorota Skowyra Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
description	Autoimmune destruction of insulin producing pancreatic β-cells is the hallmark of type I diabetes. One of the key molecules implicated in the disease onset is the immunoproteasome, a protease with multiple proteolytic sites that collaborates with the constitutive 19S and the inducible 11S (PA28) activators to produce immunogenic peptides for presentation by MHC class I molecules. Despite its importance, little is known about the function and regulation of the immunoproteasome in pancreatic β-cells. Of special interest to immunoproteasome activation in β-cells are the effects of IFNβ, a type I IFN secreted by virus-infected cells and implicated in type I diabetes onset, compared to IFNγ, the classic immunoproteasome inducer secreted by cells of the immune system. By qPCR analysis, we show that mouse insulinoma MIN6 cells and mouse islets accumulate the immune proteolytic β1(i), β2(i) and β5(i), and 11S mRNAs upon exposure to IFNβ or IFNγ. Higher concentrations of IFNβ than IFNγ are needed for similar expression, but in each case the expression is transient, with maximal mRNA accumulation in 12 hours, and depends primarily on Interferon Regulatory Factor 1. IFNs do not alter expression of regular proteasome genes, and in the time frame of IFNβ-mediated response, the immune and regular proteolytic subunits co-exist in the 20S particles. In cell extracts with ATP, these particles have normal peptidase activities and degrade polyubiquitinated proteins with rates typical of the regular proteasome, implicating normal regulation by the 19S activator. However, ATP depletion rapidly stimulates the catalytic rates in a manner consistent with levels of the 11S activator. These findings suggest that stochastic combination of regular and immune proteolytic subunits may increase the probability with which unique immunogenic peptides are produced in pancreatic β-cells exposed to IFNβ, but primarily in cells with reduced ATP levels that stimulate the 11S participation in immunoproteasome function.
format	article
author	Wieke Freudenburg Madhav Gautam Pradipta Chakraborty Jared James Jennifer Richards Alison S Salvatori Aaron Baldwin Jill Schriewer R Mark L Buller John A Corbett Dorota Skowyra
author_facet	Wieke Freudenburg Madhav Gautam Pradipta Chakraborty Jared James Jennifer Richards Alison S Salvatori Aaron Baldwin Jill Schriewer R Mark L Buller John A Corbett Dorota Skowyra
author_sort	Wieke Freudenburg
title	Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
title_short	Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
title_full	Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
title_fullStr	Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
title_full_unstemmed	Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.
title_sort	reduction in atp levels triggers immunoproteasome activation by the 11s (pa28) regulator during early antiviral response mediated by ifnβ in mouse pancreatic β-cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ce511bb44e184cc4a11634b4d99f5488
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Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.

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