Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitination and interaction with small Rab GTPases

Surface expression of chemokine receptor CXCR4 is downregulated by MIM, a member of the inverse BAR (I-BAR) domain protein family that recognizes and generates membranes with negative curvatures. Yet, the mechanism for the regulation is unknown. Here, we showed that MIM formed a complex with CXCR4 via binding to E3 ubiquitin ligase AIP4 in response to SDF-1. Overexpression of MIM promoted CXCR4 ubiquitination, inhibited cellular response to SDF-1, caused accumulation and aggregation of 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 small GTPase Rab5 at 5 min and 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 result unveiled an unprecedented property of MIM that establishes the linkage of protein ubiquitination with Rab-guided trafficking of CXCR4 in endocytic vesicles. Jo ur na l o f C el l S ci en ce • A dv an ce a rt ic le