2. Academic Validation
  3. VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling

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

  • Cell Discov. 2023 Aug 1;9(1):83. doi: 10.1038/s41421-023-00576-6.
Xiu Kui Gao # 1 2 3,  Zu Kang Sheng # 4 5,  Ye Hong Lu # 4 5,  Yu Ting Sun 4 5,  Xi Sheng Rao 4 5,  Lin Jing Shi 4 5,  Xiao Xia Cong 4 5,  Xiao Chen 5,  Hao Bo Wu 4,  Man Huang 6 7,  Qiang Zheng 4,  Jian-Sheng Guo 8,  Liang Jun Jiang 9,  Li Ling Zheng 10 11 12,  Yi Ting Zhou 13 14 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 2 International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China. [email protected].
  • 3 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].
  • 4 Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5 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.
  • 6 Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejinag, China.
  • 7 Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, 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 Biochemistry and Department of Orthopaedic Surgery of the Second 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, Zhejinag, China. [email protected].
  • 12 Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China. [email protected].
  • 13 Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 14 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].
  • 15 Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China. [email protected].
  • 16 ZJU-UoE Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 17 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
  • 18 Liangzhu Laboratory, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 37528084 DOI: 10.1038/s41421-023-00576-6
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.

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