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Published 27 March 2006. doi:10.1083/jcb.200509041
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 7, 1045-1056
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Article

 CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis

Jae-Hyuck Shim1,2, Changchun Xiao1,2, Matthew S. Hayden1,2, Ki-Young Lee1,2, E. Sergio Trombetta3, Marc Pypaert3, Atsuki Nara4, Tamotsu Yoshimori4, Bettina Wilm5, Hediye Erdjument-Bromage6, Paul Tempst6, Brigid L.M. Hogan5, Ira Mellman3, and Sankar Ghosh1,2

1 Section of Immunobiology, 2 Department of Molecular Biophysics and Biochemistry, and 3 Department of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine, New Haven, CT 06520
4 Division of Cell Genetics, National Institute for Genetics, Mishima, 411-8540, Japan
5 Department of Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232
6 Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Correspondence to Sankar Ghosh: sankar.ghosh{at}yale.edu

Charged MVB protein 5 (CHMP5) is a coiled coil protein homologous to the yeast Vps60/Mos10 gene and other ESCRT-III complex members, although its precise function in either yeast or mammalian cells is unknown. We deleted the CHMP5 gene in mice, resulting in a phenotype of early embryonic lethality, reflecting defective late endosome function and dysregulation of signal transduction. Chmp5–/– cells exhibit enlarged late endosomal compartments that contain abundant internal vesicles expressing proteins that are characteristic of late endosomes and lysosomes. This is in contrast to ESCRT-III mutants in yeast, which are defective in multivesicular body (MVB) formation. The degradative capacity of Chmp5–/– cells was reduced, and undigested proteins from multiple pathways accumulated in enlarged MVBs that failed to traffic their cargo to lysosomes. Therefore, CHMP5 regulates late endosome function downstream of MVB formation, and the loss of CHMP5 enhances signal transduction by inhibiting lysosomal degradation of activated receptors.

J.-H. Shim and C. Xiao contributed equally to this paper.

C. Xiao's present address is The CBR Institute for Biomedical Research, Boston, MA 02115.

B.L.M. Hogan's present address is Dept. of Cell Biology, Duke University Medical Center, Durham, NC 27710.

Abbreviations used in this paper: CHMP5, charged MVB protein 5; Cl-M6PR, cation-independent M6PR; E, embryonic day; EGFR, EGF receptor; ES, embryonic stem; HEK, human embryonic kidney; LAMP1, Iysosome-associated membrane protein 1; LBPA, lysobisphosphatidic acid; M6PR, mannose 6-phosphate receptor; MEF, mouse embryonic fibroblast; MHC, major histocompatibility class; MVB, multivesicular body; SARA, Smad anchor for receptor activation; shRNA, short hairpin RNA; siRNA, small interfering RNA; TßRll, TGFß receptor ll; UIM, ubiquitin-interacting motif.


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