PMID:28978524

Citation	Lear, T, Dunn, SR, McKelvey, AC, Mir, A, Evankovich, J, Chen, BB and Liu, Y (2017) RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling. Am. J. Physiol., Cell Physiol. 313:C584-C592
Abstract	As an α-chemokine receptor specific for stromal-derived-factor-1 (SDF-1, also called CXCL12), C-X-C chemokine receptor type 4 (CXCR4) plays a vital role in chemotactically attracting lymphocytes during inflammation. CXCR4 also regulates HIV infection due to its role as one of the chemokine coreceptors for HIV entry into CD4 T cells. Chemokine receptors and their signaling pathways have been shown to be regulated by the process of ubiquitination, a posttranslational modification, guided by ubiquitin E3 ligases, which covalently links ubiquitin chains to lysine residues within target substrates. Here we describe a novel mechanism regulating CXCR4 protein levels and subsequent CXCR4/CXCL12 signaling pathway through the ubiquitination and degradation of the receptor in response to ligand stimulation. We identify that an uncharacterized really interesting new gene (RING) finger ubiquitin E3 ligase, RING finger protein 113A (RNF113A), directly ubiquitinates CXCR4 in cells, leading to CXCR4 degradation, and therefore disrupts the signaling cascade. We determined that the K331 residue within CXCR4 is essential for RNF113A-mediated ubiquitin conjugation. Overexpression of RNF113A significantly reduces CXCL12-induced kinase activation in HeLa cells, whereas knockdown enhances CXCL12-induced downstream signaling. Further, RNF113A expression and silencing directly affect cell motility in a wound healing assay. These results suggest that RNF113A plays an important role in CXCR4 signaling through the ubiquitination and degradation of CXCR4. This mechanistic study might provide new understanding of HIV immunity and neutrophil activation and motility regulated by CXCR4.
Links	PubMed PMC5792167 Online version:10.1152/ajpcell.00193.2017
Keywords	DNA-Binding Proteins/metabolism; HIV Infections/immunology; HeLa Cells; Humans; Protein Stability; Receptors, CXCR4/metabolism; Signal Transduction/physiology; Ubiquitin-Protein Ligases/metabolism; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:R113A	involved_in	GO:0016567: protein ubiquitination	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:R113A	involved_in	GO:0018276: isopeptide cross-linking via N6-glycyl-L-lysine	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:R113A	involved_in	GO:0070100: negative regulation of chemokine-mediated signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:R113A	enables	GO:0061630: ubiquitin protein ligase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:R113A	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P61073	F		Seeded From UniProt	complete
HUMAN:CXCR4	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O15541	F		Seeded From UniProt	complete
HUMAN:CXCR4	involved_in	GO:0038160: CXCL12-activated CXCR4 signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:CXCR4	enables	GO:0038147: C-X-C motif chemokine 12 receptor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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