The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4 Journal Article

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Authors: Holleman, J.; Marchese, A
Article Title: The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4
Abstract: G protein-coupled receptor (GPCR) sorting into the degradative pathway is important for limiting the duration and magnitude of signaling. Agonist activation of the GPCR CXCR4 induces its rapid ubiquitination and sorting to lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. We recently reported that ESCRT-0 ubiquitination is linked to the efficiency with which CXCR4 is sorted for lysosomal degradation; however mechanistic insight is lacking. Here we define a novel role for the really interesting new gene-domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes. We show that DTX3L localizes to early endosomes upon CXCR4 activation and interacts directly with and inhibits the activity of the E3 ubiquitin ligase atrophin-1 interacting protein 4. This serves to limit the extent to which ESCRT-0 is ubiquitinated and is able to sort CXCR4 for lysosomal degradation. Therefore we define a novel role for DTX3L in GPCR endosomal sorting and reveal an unprecedented link between two distinct E3 ubiquitin ligases to control the activity of the ESCRT machinery.
Journal Title: Molecular biology of the cell
Volume: 25
Issue: 12
ISSN: 1939-4586; 1059-1524
Publisher: Holleman and Marchese. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution-Noncommercial-Share Alike 3.0 Unported (TRUNCATED  
Journal Place: United States
Date Published: 2014
Start Page: 1892
End Page: 1904
Language: eng
DOI/URL:

10.1091/mbc.E13-10-0612
Notes: LR: 20141215; CI: (c) 2014; GR: GM106727/GM/NIGMS NIH HHS/United States; GR: R01 GM106727/GM/NIGMS NIH HHS/United States; JID: 9201390; 0 (Adaptor Proteins, Signal Transducing); 0 (CXCR4 protein, human); 0 (DTX3L protein, human); 0 (Endosomal Sorting Complexes Required for Transport); 0 (Phosphoproteins); 0 (Receptors, CXCR4); 0 (Repressor Proteins); 0 (STAM protein, human); EC 6.3.2.19 (ITCH protein, human); EC 6.3.2.19 (Ubiquitin-Protein Ligases); OID: NLM: PMC4055268; 2014/04/30 [aheadofprint]; ppublish