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PMID: 17116753 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transport of LAPTM5 to lysosomes requires association with the ubiquitin ligase Nedd4, but not LAPTM5 ubiquitination.

The Journal of cell biology ·Vol. 175 ·No. 4 ·2006-11-20 ·Pages 631-45

Pak Y, Glowacka WK, Bruce MC, Pham N, Rotin D

Abstract

LAPTM5 is a lysosomal transmembrane protein expressed in immune cells. We show that LAPTM5 binds the ubiquitin-ligase Nedd4 and GGA3 to promote LAPTM5 sorting from the Golgi to the lysosome, an event that is independent of LAPTM5 ubiquitination. LAPTM5 contains three PY motifs (L/PPxY), which bind Nedd4-WW domains, and a ubiquitin-interacting motif (UIM) motif. The Nedd4-LAPTM5 complex recruits ubiquitinated GGA3, which binds the LAPTM5-UIM; this interaction does not require the GGA3-GAT domain. LAPTM5 mutated in its Nedd4-binding sites (PY motifs) or its UIM is retained in the Golgi, as is LAPTM5 expressed in cells in which Nedd4 or GGA3 is knocked-down with RNAi. However, ubiquitination-impaired LAPTM5 can still traffic to the lysosome, suggesting that Nedd4 binding to LAPTM5, not LAPTM5 ubiquitination, is required for targeting. Interestingly, Nedd4 is also able to ubiquitinate GGA3. These results demonstrate a novel mechanism by which the ubiquitin-ligase Nedd4, via interactions with GGA3 and cargo (LAPTM5), regulates cargo trafficking to the lysosome without requiring cargo ubiquitination.

MeSH Terms
ADP-Ribosylation Factors/chemistry Adaptor Proteins, Vesicular Transport/chemistry Amino Acid Motifs Animals Dendritic Cells/ultrastructure Endosomal Sorting Complexes Required for Transport Golgi Apparatus/ultrastructure Humans Lysosomes/metabolism,ultrastructure Membrane Proteins/chemistry,metabolism Mice Models, Biological Mutant Proteins/chemistry Nedd4 Ubiquitin Protein Ligases Protein Binding Protein Transport Ubiquitin/metabolism Ubiquitin-Protein Ligases/chemistry,deficiency,metabolism
Chemicals
Adaptor Proteins, Vesicular Transport Endosomal Sorting Complexes Required for Transport GGA adaptor proteins Membrane Proteins Mutant Proteins Ubiquitin Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Nedd4l protein, mouse Ubiquitin-Protein Ligases ADP-Ribosylation Factors
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Pak Youngshil
Program in Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, M5G 1X8.
Glowacka Wioletta K
Bruce M Christine
Pham Nam
Rotin Daniela
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200603001
Published
2006-11-20
Pages
631-45
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2064599
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200603001 PMC Full Text View journal details
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