VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling
Abstract 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,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00576-6 |
| _version_ | 1797752842693378048 |
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| author | Xiu Kui Gao Zu Kang Sheng Ye Hong Lu Yu Ting Sun Xi Sheng Rao Lin Jing Shi Xiao Xia Cong Xiao Chen Hao Bo Wu Man Huang Qiang Zheng Jian-sheng Guo Liang Jun Jiang Li Ling Zheng Yi Ting Zhou |
| author_facet | Xiu Kui Gao Zu Kang Sheng Ye Hong Lu Yu Ting Sun Xi Sheng Rao Lin Jing Shi Xiao Xia Cong Xiao Chen Hao Bo Wu Man Huang Qiang Zheng Jian-sheng Guo Liang Jun Jiang Li Ling Zheng Yi Ting Zhou |
| author_sort | Xiu Kui Gao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T17:10:19Z |
| format | Article |
| id | doaj.art-750a3b7e14b6488496e3dbd0be4e9768 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-12T17:10:19Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-750a3b7e14b6488496e3dbd0be4e97682023-08-06T11:06:31ZengNature Publishing GroupCell Discovery2056-59682023-08-019111810.1038/s41421-023-00576-6VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signalingXiu Kui Gao0Zu Kang Sheng1Ye Hong Lu2Yu Ting Sun3Xi Sheng Rao4Lin Jing Shi5Xiao Xia Cong6Xiao Chen7Hao Bo Wu8Man Huang9Qiang Zheng10Jian-sheng Guo11Liang Jun Jiang12Li Ling Zheng13Yi Ting Zhou14Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pathology of Sir Run Run Shaw Hospital, Center of Cryo-Electron Microscopy, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineAbstract 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.https://doi.org/10.1038/s41421-023-00576-6 |
| spellingShingle | Xiu Kui Gao Zu Kang Sheng Ye Hong Lu Yu Ting Sun Xi Sheng Rao Lin Jing Shi Xiao Xia Cong Xiao Chen Hao Bo Wu Man Huang Qiang Zheng Jian-sheng Guo Liang Jun Jiang Li Ling Zheng Yi Ting Zhou VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling Cell Discovery |
| 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 |
| url | https://doi.org/10.1038/s41421-023-00576-6 |
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