Document Type
Article
Publication Date
12-30-2021
Abstract
WHIM syndrome is a rare immunodeficiency disorder that is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. Here, we report on a new WHIM syndrome mutation that results in a frame shift within the codon for Ser339 (S339fs5) and compare the properties of S339fs5 with wild-type CXCR4 and a previously identified WHIM syndrome mutant, R334X. The S339fs5 and R334X mutants exhibited significantly increased signaling compared to wild-type CXCR4 including agonist-promoted calcium flux and extracellular-signal-regulated kinase activation. This increase is at least partially due to a significant decrease in agonist-promoted phosphorylation, β-arrestin binding, and endocytosis of S339fs5 and R334X compared with wild-type CXCR4. Interestingly, there were also significant differences in receptor degradation, with S339fs5 having a very high basal level of degradation compared with that of R334X and wild-type CXCR4. In contrast to wild-type CXCR4, both R334X and S339fs5 were largely insensitive to CXCL12-promoted degradation. Moreover, while basal and agonist-promoted degradation of wild-type CXCR4 was effectively inhibited by the CXCR4 antagonist TE-14016, this had no effect on the degradation of the WHIM mutants. Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, which promotes enhanced signaling, reduced phosphorylation, β-arrestin binding and endocytosis, and a very high basal rate of degradation that is not protected by antagonist treatment.
Recommended Citation
Luo, Jiansong; De Pascali, Francesco; Richmond, G Wendell; Khojah, Amer M; and Benovic, Jeffrey L, "Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor CXCR4" (2021). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 203.
https://jdc.jefferson.edu/bmpfp/203
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
34973340
Language
English
Comments
This article is the author’s final published version in Journal of Biological Chemistry, Volume 298, Issue 21 February 2022 Article number 101551.
The published version is available at https://doi.org/10.1016/j.jbc.2021.101551. Copyright © Luo et al.