Involvement of vps33a in the fusion of uroplakin-degrading multivesicular bodies with lysosomes.
The apical surface of the terminally differentiated mouse bladder urothelium is largely covered by urothelial plaques, consisting of hexagonally packed 16-nm uroplakin particles. These plaques are delivered to the cell surface by fusiform vesicles (FVs) that are the most abundant cytoplasmic organelles. We have analyzed the functional involvement of several proteins in the apical delivery and endocytic degradation of uroplakin proteins. Although FVs have an acidified lumen and Rab27b, which localizes to these organelles, is known to be involved in the targeting of lysosome-related organelles (LROs), FVs are CD63 negative and are therefore not typical LROs. Vps33a is a Sec1-related protein that plays a role in vesicular transport to the lysosomal compartment. A point mutation in mouse Vps33a (Buff mouse) causes albinism and bleeding (Hermansky-Pudlak syndrome) because of abnormalities in the trafficking of melanosomes and platelets. These Buff mice showed a novel phenotype observed in urothelial umbrella cells, where the uroplakin-delivering FVs were almost completely replaced by Rab27b-negative multivesicular bodies (MVBs) involved in uroplakin degradation. MVB accumulation leads to an increase in the amounts of uroplakins, Lysosomal-associated membrane protein (LAMP)-1/2, and the activities of beta-hexosaminidase and beta-glucocerebrosidase. These results suggest that FVs can be regarded as specialized secretory granules that deliver crystalline arrays of uroplakins to the cell surface, and that the Vps33a mutation interferes with the fusion of MVBs with mature lysosomes thus blocking uroplakin degradation.
Guo
Xuemei
X
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Tu
Liyu
L
Gumper
Iwona
I
Plesken
Heide
H
Novak
Edward K
EK
Chintala
Sreenivasulu
S
Swank
Richard T
RT
Pastores
Gregory
G
Torres
Paola
P
Izumi
Tetsuro
T
Sun
Tung-Tien
TT
Sabatini
David D
DD
Kreibich
Gert
G
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016253:Microscopy, Immunoelectron; D057146:Multivesicular Bodies / Q000378:metabolism* / Q000648:ultrastructure; D017354:Point Mutation; D021381:Protein Transport; D001743:Urinary Bladder / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D060170:Uroplakin II; D060171:Uroplakin III; D019459:Urothelium / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D060171:Uroplakin III; D033921:Vesicular Transport Proteins; C472129:Vps33a protein, mouse; C512958:Rab27b protein, mouse; D020691:rab GTP-Binding Proteins