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

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.

• Publication year

  2006

• Venue

  Journal of Cell Biology

• Publication date

  2006-11-20

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1083/jcb.200603001PMID 17116753PMCID 2064599
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Interactions of GGA3 with the ubiquitin sorting machinery

  2004influential reference
• The GGA proteins: adaptors on the move

  2004influential reference
• Membrane traffic: GGAs sort ubiquitin.

  2004cited by this paper
• GAT (GGA and Tom1) Domain Responsible for Ubiquitin Binding and Ubiquitination*

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• Receptor downregulation and multivesicular-body sorting

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• A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins

  2002influential reference
• Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains

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• Lysosome-associated protein transmembrane 4 alpha (LAPTM4 alpha) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes.

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• Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis

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• A Mammalian Lysosomal Membrane Protein Confers Multidrug Resistance upon Expression in Saccharomyces cerevisiae *

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• Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body.

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• A function for monoubiquitination in the internalization of a G protein-coupled receptor.

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• c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor.

  1998cited by this paper
• Immunolocalization of the ubiquitin-protein ligase Nedd4 in tissues expressing the epithelial Na+ channel (ENaC).

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• Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules.

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• WW domains of Nedd4 bind to the proline‐rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.

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• E3, a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha.

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• Identification of a Novel Membrane Transporter Associated with Intracellular Membranes by Phenotypic Complementation in the Yeast Saccharomyces cerevisiae(*)

  1996cited by this paper
• LAPTM5: a novel lysosomal-associated multispanning membrane protein preferentially expressed in hematopoietic cells.

  1996influential reference
• Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain.

  1994cited by this paper

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