VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Cell discovery - 9(2023), 1 vom: 01. Aug., Seite 83 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Xiu Kui [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 04.08.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1038/s41421-023-00576-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360278612 |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Sheng, Zu Kang |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Ye Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yu Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Xi Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Lin Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Cong, Xiao Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Hao Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Man |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Jian-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Liang Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Li Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yi Ting |e verfasserin |4 aut | |
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