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VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling

The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains p...

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Autores principales: Gao, Xiu Kui, Sheng, Zu Kang, Lu, Ye Hong, Sun, Yu Ting, Rao, Xi Sheng, Shi, Lin Jing, Cong, Xiao Xia, Chen, Xiao, Wu, Hao Bo, Huang, Man, Zheng, Qiang, Guo, Jian-sheng, Jiang, Liang Jun, Zheng, Li Ling, Zhou, Yi Ting
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394085/
https://www.ncbi.nlm.nih.gov/pubmed/37528084
http://dx.doi.org/10.1038/s41421-023-00576-6
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author Gao, Xiu Kui
Sheng, Zu Kang
Lu, Ye Hong
Sun, Yu Ting
Rao, Xi Sheng
Shi, Lin Jing
Cong, Xiao Xia
Chen, Xiao
Wu, Hao Bo
Huang, Man
Zheng, Qiang
Guo, Jian-sheng
Jiang, Liang Jun
Zheng, Li Ling
Zhou, Yi Ting
author_facet Gao, Xiu Kui
Sheng, Zu Kang
Lu, Ye Hong
Sun, Yu Ting
Rao, Xi Sheng
Shi, Lin Jing
Cong, Xiao Xia
Chen, Xiao
Wu, Hao Bo
Huang, Man
Zheng, Qiang
Guo, Jian-sheng
Jiang, Liang Jun
Zheng, Li Ling
Zhou, Yi Ting
author_sort Gao, Xiu Kui
collection PubMed
description The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.
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spelling pubmed-103940852023-08-03 VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling Gao, Xiu Kui Sheng, Zu Kang Lu, Ye Hong Sun, Yu Ting Rao, Xi Sheng Shi, Lin Jing Cong, Xiao Xia Chen, Xiao Wu, Hao Bo Huang, Man Zheng, Qiang Guo, Jian-sheng Jiang, Liang Jun Zheng, Li Ling Zhou, Yi Ting Cell Discov Article The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane. Springer Nature Singapore 2023-08-01 /pmc/articles/PMC10394085/ /pubmed/37528084 http://dx.doi.org/10.1038/s41421-023-00576-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gao, Xiu Kui
Sheng, Zu Kang
Lu, Ye Hong
Sun, Yu Ting
Rao, Xi Sheng
Shi, Lin Jing
Cong, Xiao Xia
Chen, Xiao
Wu, Hao Bo
Huang, Man
Zheng, Qiang
Guo, Jian-sheng
Jiang, Liang Jun
Zheng, Li Ling
Zhou, Yi Ting
VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title_full VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title_fullStr VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title_full_unstemmed VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title_short VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
title_sort vapb-mediated er-targeting stabilizes irs-1 signalosomes to regulate insulin/igf signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394085/
https://www.ncbi.nlm.nih.gov/pubmed/37528084
http://dx.doi.org/10.1038/s41421-023-00576-6
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