Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes
Abstract As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this rema...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-022-00426-x |
| _version_ | 1818488372628291584 |
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| author | Xiu Kui Gao Xi Sheng Rao Xiao Xia Cong Zu Kang Sheng Yu Ting Sun Shui Bo Xu Jian Feng Wang Yong Heng Liang Lin Rong Lu Hongwei Ouyang Huiqing Ge Jian-sheng Guo Hang-jun Wu Qi Ming Sun Hao-bo Wu Zhang Bao Li Ling Zheng Yi Ting Zhou |
| author_facet | Xiu Kui Gao Xi Sheng Rao Xiao Xia Cong Zu Kang Sheng Yu Ting Sun Shui Bo Xu Jian Feng Wang Yong Heng Liang Lin Rong Lu Hongwei Ouyang Huiqing Ge Jian-sheng Guo Hang-jun Wu Qi Ming Sun Hao-bo Wu Zhang Bao Li Ling Zheng Yi Ting Zhou |
| author_sort | Xiu Kui Gao |
| collection | DOAJ |
| description | Abstract As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases. |
| first_indexed | 2024-12-10T16:50:15Z |
| format | Article |
| id | doaj.art-61e3a10be1d3437791635da611d63910 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-12-10T16:50:15Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-61e3a10be1d3437791635da611d639102022-12-22T01:40:55ZengNature Publishing GroupCell Discovery2056-59682022-06-018111910.1038/s41421-022-00426-xPhase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomesXiu Kui Gao0Xi Sheng Rao1Xiao Xia Cong2Zu Kang Sheng3Yu Ting Sun4Shui Bo Xu5Jian Feng Wang6Yong Heng Liang7Lin Rong Lu8Hongwei Ouyang9Huiqing Ge10Jian-sheng Guo11Hang-jun Wu12Qi Ming Sun13Hao-bo Wu14Zhang Bao15Li Ling Zheng16Yi Ting Zhou17Department 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 Respiratory Medicine, the First Affiliated Hospital, Zhejiang University School of MedicineCollege of Life Sciences, Key Laboratory of Agricultural Environmental Microbiology of Ministry of Agriculture, Nanjing Agricultural UniversityDr. 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 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 Respiratory Care, Regional Medical Center for the National Institute of Respiratory Diseases, Sir Run Run Shaw 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 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 MedicineDepartment of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Medicine, the First 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 As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.https://doi.org/10.1038/s41421-022-00426-x |
| spellingShingle | Xiu Kui Gao Xi Sheng Rao Xiao Xia Cong Zu Kang Sheng Yu Ting Sun Shui Bo Xu Jian Feng Wang Yong Heng Liang Lin Rong Lu Hongwei Ouyang Huiqing Ge Jian-sheng Guo Hang-jun Wu Qi Ming Sun Hao-bo Wu Zhang Bao Li Ling Zheng Yi Ting Zhou Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes Cell Discovery |
| title | Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes |
| title_full | Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes |
| title_fullStr | Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes |
| title_full_unstemmed | Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes |
| title_short | Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes |
| title_sort | phase separation of insulin receptor substrate 1 drives the formation of insulin igf 1 signalosomes |
| url | https://doi.org/10.1038/s41421-022-00426-x |
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