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PMID:28978524

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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

Significance

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

Notes

See also

References

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