Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila

Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila us...

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Autores principales:	Tatsuki Yamazoe, Yasuyuki Nakahara, Hiroka Katsube, Yoshihiro H. Inoue
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ER stress <i>Gadd45</i> JNK diabetes NDM <i>Drosophila</i> Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/526e22f66d1c40a28195b49a6c45a81f
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spelling	oai:doaj.org-article:526e22f66d1c40a28195b49a6c45a81f2021-11-11T17:26:15ZExpression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>10.3390/ijms2221120381422-00671661-6596https://doaj.org/article/526e22f66d1c40a28195b49a6c45a81f2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12038https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in <i>Drosophila</i> using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS<sup>C96Y</sup> and hINS<sup>LB15YB16delinsH</sup>, neither of which secreted from the β-cells, could not stimulate the <i>Drosophila</i> growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent <i>Xbp1</i> mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of <i>Growth arrest and DNA-damage-inducible 45</i> (<i>Gadd45</i>) in imaginal disc cells. ER stress induced by hINS<sup>C96Y</sup> also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.Tatsuki YamazoeYasuyuki NakaharaHiroka KatsubeYoshihiro H. InoueMDPI AGarticleER stress<i>Gadd45</i>JNKdiabetesNDM<i>Drosophila</i>Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12038, p 12038 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ER stress <i>Gadd45</i> JNK diabetes NDM <i>Drosophila</i> Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ER stress <i>Gadd45</i> JNK diabetes NDM <i>Drosophila</i> Biology (General) QH301-705.5 Chemistry QD1-999 Tatsuki Yamazoe Yasuyuki Nakahara Hiroka Katsube Yoshihiro H. Inoue Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
description	Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in <i>Drosophila</i> using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS<sup>C96Y</sup> and hINS<sup>LB15YB16delinsH</sup>, neither of which secreted from the β-cells, could not stimulate the <i>Drosophila</i> growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent <i>Xbp1</i> mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of <i>Growth arrest and DNA-damage-inducible 45</i> (<i>Gadd45</i>) in imaginal disc cells. ER stress induced by hINS<sup>C96Y</sup> also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.
format	article
author	Tatsuki Yamazoe Yasuyuki Nakahara Hiroka Katsube Yoshihiro H. Inoue
author_facet	Tatsuki Yamazoe Yasuyuki Nakahara Hiroka Katsube Yoshihiro H. Inoue
author_sort	Tatsuki Yamazoe
title	Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
title_short	Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
title_full	Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
title_fullStr	Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
title_full_unstemmed	Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>
title_sort	expression of human mutant preproinsulins induced unfolded protein response, <i>gadd45</i> expression, jak-stat activation, and growth inhibition in <i>drosophila</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/526e22f66d1c40a28195b49a6c45a81f
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Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, <i>Gadd45</i> Expression, JAK-STAT Activation, and Growth Inhibition in <i>Drosophila</i>

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