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1000
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Abstract/Summary
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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 IRS1. 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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