The complex nature of CXCR4 mutations in WHIM syndrome

Front Immunol. 2024 Jul 5:15:1406532. doi: 10.3389/fimmu.2024.1406532. eCollection 2024.

Abstract

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.

Keywords: CXCL12; CXCR4; WHIM syndrome; receptor conformations; signaling pathways; β-arrestins.

Publication types

  • Review

MeSH terms

  • Animals
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism
  • Humans
  • Mutation*
  • Primary Immunodeficiency Diseases* / genetics
  • Receptors, CXCR4* / genetics
  • Receptors, CXCR4* / metabolism
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology
  • Signal Transduction*
  • Thrombocytopenia / genetics
  • Warts* / genetics

Substances

  • Receptors, CXCR4
  • CXCR4 protein, human
  • Chemokine CXCL12

Supplementary concepts

  • WHIM syndrome

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Spanish Ministry of Science and Innovation (PID2020-114980RB-I00 supported by MCIN/AEI/10.13039/501100011033/FEDER, UE) to MM and (PID2022-140651NB-I00 supported by MCIN/AEI/10.13039/501100011033/FEDER, UE) to CS and from the Biomedicine Program of the Regional Government of Comunidad de Madrid, Spain (S2022/BMD-7274 RETAR-A-COVID-CM) to MM.