ILDR2 stabilization is regulated by its interaction with GRP78

Abstract Ildr2 was initially identified as a genetic modifier of diabetes susceptibility in B6.DBA Lep ob congenic mice, and was associated with decreased β-cell replication rates, reduced β-cell mass, and persistent mild hypoinsulinemic hyperglycemia. However, the molecular mechanisms of how the I...

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Autores principales:	Kazuhisa Watanabe, Kazuhiro Nakayama, Satoshi Ohta, Ayumi Matsumoto, Hidetoshi Tsuda, Sadahiko Iwamoto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/04dd66a84d6c4d78bf181fad4c433081
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spelling	oai:doaj.org-article:04dd66a84d6c4d78bf181fad4c4330812021-12-02T14:26:20ZILDR2 stabilization is regulated by its interaction with GRP7810.1038/s41598-021-87884-72045-2322https://doaj.org/article/04dd66a84d6c4d78bf181fad4c4330812021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87884-7https://doaj.org/toc/2045-2322Abstract Ildr2 was initially identified as a genetic modifier of diabetes susceptibility in B6.DBA Lep ob congenic mice, and was associated with decreased β-cell replication rates, reduced β-cell mass, and persistent mild hypoinsulinemic hyperglycemia. However, the molecular mechanisms of how the ILDR2 protein is involved in these effects are largely unknown. We sought to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underpinning ILDR2 function in pancreatic β-cells. Using TAP tag technology, we purified proteins interacting with ILDR2 in the pancreatic β-cell line MIN6, and identified the endoplasmic reticulum resident chaperones, GRP78 and PDIA1, as novel proteins interacting with ILDR2. We demonstrated that GRP78 interacted with ILDR2 and was possibly involved in ILDR2 stabilization by inhibiting ubiquitin–proteasome degradation. Additionally, adenoviral ILDR2 knockdown led to reduced glucose-responsive insulin secretion in MIN6 β-cells, suggesting ILDR2 may be implicated in a new pathway in hypoinsulinemic hyperglycemia. These data provide evidence for a novel association between GRP78 and ILDR2, and suggest GPR78-ILDR2 may a novel target for diabetic therapeutic modulation in decreased insulin secretion.Kazuhisa WatanabeKazuhiro NakayamaSatoshi OhtaAyumi MatsumotoHidetoshi TsudaSadahiko IwamotoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kazuhisa Watanabe Kazuhiro Nakayama Satoshi Ohta Ayumi Matsumoto Hidetoshi Tsuda Sadahiko Iwamoto ILDR2 stabilization is regulated by its interaction with GRP78
description	Abstract Ildr2 was initially identified as a genetic modifier of diabetes susceptibility in B6.DBA Lep ob congenic mice, and was associated with decreased β-cell replication rates, reduced β-cell mass, and persistent mild hypoinsulinemic hyperglycemia. However, the molecular mechanisms of how the ILDR2 protein is involved in these effects are largely unknown. We sought to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underpinning ILDR2 function in pancreatic β-cells. Using TAP tag technology, we purified proteins interacting with ILDR2 in the pancreatic β-cell line MIN6, and identified the endoplasmic reticulum resident chaperones, GRP78 and PDIA1, as novel proteins interacting with ILDR2. We demonstrated that GRP78 interacted with ILDR2 and was possibly involved in ILDR2 stabilization by inhibiting ubiquitin–proteasome degradation. Additionally, adenoviral ILDR2 knockdown led to reduced glucose-responsive insulin secretion in MIN6 β-cells, suggesting ILDR2 may be implicated in a new pathway in hypoinsulinemic hyperglycemia. These data provide evidence for a novel association between GRP78 and ILDR2, and suggest GPR78-ILDR2 may a novel target for diabetic therapeutic modulation in decreased insulin secretion.
format	article
author	Kazuhisa Watanabe Kazuhiro Nakayama Satoshi Ohta Ayumi Matsumoto Hidetoshi Tsuda Sadahiko Iwamoto
author_facet	Kazuhisa Watanabe Kazuhiro Nakayama Satoshi Ohta Ayumi Matsumoto Hidetoshi Tsuda Sadahiko Iwamoto
author_sort	Kazuhisa Watanabe
title	ILDR2 stabilization is regulated by its interaction with GRP78
title_short	ILDR2 stabilization is regulated by its interaction with GRP78
title_full	ILDR2 stabilization is regulated by its interaction with GRP78
title_fullStr	ILDR2 stabilization is regulated by its interaction with GRP78
title_full_unstemmed	ILDR2 stabilization is regulated by its interaction with GRP78
title_sort	ildr2 stabilization is regulated by its interaction with grp78
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/04dd66a84d6c4d78bf181fad4c433081
work_keys_str_mv	AT kazuhisawatanabe ildr2stabilizationisregulatedbyitsinteractionwithgrp78 AT kazuhironakayama ildr2stabilizationisregulatedbyitsinteractionwithgrp78 AT satoshiohta ildr2stabilizationisregulatedbyitsinteractionwithgrp78 AT ayumimatsumoto ildr2stabilizationisregulatedbyitsinteractionwithgrp78 AT hidetoshitsuda ildr2stabilizationisregulatedbyitsinteractionwithgrp78 AT sadahikoiwamoto ildr2stabilizationisregulatedbyitsinteractionwithgrp78
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ILDR2 stabilization is regulated by its interaction with GRP78

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