CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis.
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.
Section of Immunobiology, Ludwig Institute for Cancer Research, Yale University School of Medicine, New Haven, CT 06520, USA.
Jae-Hyuck
JH
Shim
Changchun
C
Xiao
Matthew S
MS
Hayden
Ki-Young
KY
Lee
E Sergio
ES
Trombetta
Marc
M
Pypaert
Atsuki
A
Nara
Tamotsu
T
Yoshimori
Bettina
B
Wilm
Hediye
H
Erdjument-Bromage
Paul
P
Tempst
Brigid L M
BL
Hogan
Ira
I
Mellman
Sankar
S
Ghosh
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism; D014162:Transfection
C511082:CHMP5 protein, mouse; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D006735:Horseradish Peroxidase; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II