Late endosome motility depends on lipids via the small GTPase Rab7.
We report that lipids contribute to regulate the bidirectional motility of late endocytic compartments. Late endocytic vesicles loaded with cholesterol lose their dynamic properties, and become essentially immobile, including in cells from Niemann-Pick C patients. These vesicles then retain cytoplasmic dynein activity, but seem to be unable to acquire kinesin activity, eventually leading to paralysis. Our data suggest that this defect depends on the small GTPase Rab7, since the motility of vesicles loaded with cholesterol can be restored by the Rab7 inhibitory mutant N125I. Conversely, wild-type Rab7 overexpression mimics the effects of cholesterol on motility in control cells. Consistently, cholesterol accumulation increases the amounts of membrane-associated Rab7, and inhibits Rab7 membrane extraction by the guanine nucleotide dissociation inhibitor. Our observations thus indicate that cholesterol contributes to regulate the Rab7 cycle, and that Rab7 in turn controls the net movement of late endocytic elements. We conclude that motor functions can be regulated by the membrane lipid composition via the Rab7 cycle.
Lebrand
Cécile
C
Department of Biochemistry, University of Geneva, Sciences II, 1211 Geneva 4, Switzerland.
Corti
Michela
M
Goodson
Holly
H
Cosson
Pierre
P
Cavalli
Valeria
V
Mayran
Nathalie
N
Fauré
Julien
J
Gruenberg
Jean
J
D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002451:Cell Compartmentation; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D000072159:Dynactin Complex; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D049452:Green Fluorescent Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D050178:Monoglycerides; D009542:Niemann-Pick Diseases / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D060149:Tetraspanin 30; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
D000736:Androstenes; D000924:Anticholesteremic Agents; D015703:Antigens, CD; C554586:CD63 protein, human; D000072159:Dynactin Complex; D020730:Guanine Nucleotide Dissociation Inhibitors; D008164:Luminescent Proteins; D008246:Lysophospholipids; D008869:Microtubule-Associated Proteins; D050178:Monoglycerides; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D060149:Tetraspanin 30; C012786:bis(monoacylglyceryl)phosphate; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D049452:Green Fluorescent Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D016547:Kinesins; D020691:rab GTP-Binding Proteins