title: Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases.
abstract: Surface expression of chemokine receptor CXCR4 is downregulated by missing-in-metastasis protein (MIM; also known as MTSS1), a member of the inverse BAR (I-BAR)-domain protein family that recognizes and generates membranes with negative curvature. Yet, the mechanism for the regulation is unknown. Here, we show that MIM forms a complex with CXCR4 by binding to E3 ubiquitin ligase AIP4 (also known as ITCH) in response to stromal cell-derived factor 1 (SDF-1; also known as CXCL12). Overexpression of MIM promoted CXCR4 ubiquitylation, inhibited cellular response to SDF-1, caused accumulation and aggregation of multivesicular bodies (MVBs) in the cytoplasm, and promoted CXCR4 sorting into MVBs in a manner depending on binding to AIP4. In response to SDF-1, MIM also bound transiently to the small GTPase Rab5 at 5 min and to Rab7 at 30 min. Binding to Rab7 requires an N-terminal coiled-coil motif, deletion of which abolished MIM-mediated MVB formation and CXCR4 internalization. Our results unveil a previously unknown property of MIM that establishes the linkage of protein ubiquitylation with Rab-guided trafficking of CXCR4 in endocytic vesicles.
authors.affiliation: School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.|Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Lushen
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Shaneen S
authors.initials: SS
authors.lastname: Baxter
authors.affiliation: School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Ning
authors.identifier: 0000-0003-0047-337X
authors.initials: N
authors.lastname: Gu
authors.affiliation: School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA xzhan@som.umaryland.edu.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.
authors.forename: Xi
authors.identifier: 0000-0003-3291-3050
authors.initials: X
authors.lastname: Zhan
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D019718:Receptors, CXCR4 / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism; D054875:Ubiquitination; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D020691:rab GTP-Binding Proteins
keywords: AIP4; CXCR4; MIM; MVBs; Rab7; Ubiquitylation