Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes

  • Cell Discov. 2022 Jun 28;8(1):60. doi: 10.1038/s41421-022-00426-x.
Xiu Kui Gao   #  1  2 ,  Xi Sheng Rao   #  1  2 ,  Xiao Xia Cong   #  1  2 ,  Zu Kang Sheng   #  1  2 ,  Yu Ting Sun  1  2 ,  Shui Bo Xu  1  2  3 ,  Jian Feng Wang  4 ,  Yong Heng Liang  5 ,  Lin Rong Lu  2  3  6 ,  Hongwei Ouyang  2  3 ,  Huiqing Ge  7 ,  Jian-Sheng Guo  8 ,  Hang-Jun Wu  8 ,  Qi Ming Sun  1 ,  Hao-Bo Wu  1 ,  Zhang Bao  9 ,  Li Ling Zheng  10  11 ,  Yi Ting Zhou  12  13  14
Affiliations
  • 1. Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2. Dr. 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 Medicine, Hangzhou, Zhejiang, China.
  • 3. ZJU-UoE Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4. Department of Respiratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5. College of Life Sciences, Key Laboratory of Agricultural Environmental Microbiology of Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, China.
  • 6. Department of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 7. Department of Respiratory Care, Regional Medical Center for the National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 8. Department of Pathology of Sir Run Run Shaw Hospital, Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 9. Department of Respiratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 10. Dr. 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 Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 11. Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 12. Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 13. Dr. 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 Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 14. ZJU-UoE Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 35764611 DOI: 10.1038/s41421-022-00426-x
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.

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