CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

Stéphane M Camus, Marine D Camus, Carmen Figueras-Novoa, Gaelle Boncompain, L Amanda Sadacca, Christopher Esk, Anne Bigot, Gwyn W Gould, Dimitrios Kioumourtzoglou, Franck Perez, Nia J Bryant, Shaeri Mukherjee, Frances M Brodsky

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Glucose transporter 4 (GLUT4) is sequestered inside muscle and fat and then released by vesicle traffic to the cell surface in response to postprandial insulin for blood glucose clearance. Here, we map the biogenesis of this GLUT4 traffic pathway in humans, which involves clathrin isoform CHC22. We observe that GLUT4 transits through the early secretory pathway more slowly than the constitutively secreted GLUT1 transporter and localize CHC22 to the ER-to-Golgi intermediate compartment (ERGIC). CHC22 functions in transport from the ERGIC, as demonstrated by an essential role in forming the replication vacuole of Legionella pneumophila bacteria, which requires ERGIC-derived membrane. CHC22 complexes with ERGIC tether p115, GLUT4, and sortilin, and downregulation of either p115 or CHC22, but not GM130 or sortilin, abrogates insulin-responsive GLUT4 release. This indicates that CHC22 traffic initiates human GLUT4 sequestration from the ERGIC and defines a role for CHC22 in addition to retrograde sorting of GLUT4 after endocytic recapture, enhancing pathways for GLUT4 sequestration in humans relative to mice, which lack CHC22.

Original languageEnglish
Article numbere201812135
Number of pages21
JournalJournal of Cell Biology
Issue number1
Early online date19 Dec 2019
Publication statusPublished - 6 Jan 2020

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  • Adaptor Proteins, Vesicular Transport/metabolism
  • Biosynthetic Pathways
  • Cell Membrane/metabolism
  • Clathrin/metabolism
  • Clathrin Heavy Chains/metabolism
  • Endoplasmic Reticulum/metabolism
  • Glucose Transporter Type 4/metabolism
  • Golgi Apparatus/metabolism
  • HeLa Cells
  • Humans
  • Protein Transport
  • Rho Guanine Nucleotide Exchange Factors/metabolism
  • Vesicular Transport Proteins/metabolism

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