PMID- 37141381
OWN - NLM
STAT- MEDLINE
DCOM- 20230508
LR  - 20231124
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 18
IP  - 5
DP  - 2023
TI  - The N-terminus of CXCR4 splice variants determines expression and functional 
      properties.
PG  - e0283015
LID - 10.1371/journal.pone.0283015 [doi]
LID - e0283015
AB  - C-X-C motif chemokine ligand 12(CXCL12) is an essential chemokine for organ 
      development and homeostasis in multiple tissues. Its receptor, C-X-C chemokine 
      receptor type 4(CXCR4), is expressed on the surface of target cells. The 
      chemokine and receptor are expressed almost ubiquitously in human tissues and 
      cells throughout life, and abnormal expression of CXCL12 and CXCR4 is observed in 
      pathological conditions, such as inflammation and cancer. CXCR4 is reportedly 
      translated into five splicing variants of different lengths, which each have 
      different amino acids in the N-terminus. As the N-terminus is the first 
      recognition site for chemokines, CXCR4 variants may respond differently to 
      CXCL12. Despite these differences, the molecular and functional properties of 
      CXCR4 variants have not been thoroughly described or compared. Here, we explored 
      the expression of CXCR4 variants in cell lines and analyzed their roles in 
      cellular responses using biochemical approaches. RT-PCR revealed that most cell 
      lines express more than one CXCR4 variant. When expressed in HEK293 cells, the 
      CXCR4 variants differed in protein expression efficiency and cell surface 
      localization. Although variant 2 demonstrated the strongest expression and cell 
      surface localization, variants 1, 3, and 5 also mediated chemokine signaling and 
      induced cellular responses. Our results demonstrate that the N-terminal sequences 
      of each CXCR4 variant determine the expression of the receptor and affect ligand 
      recognition. Functional analyses revealed that CXCR4 variants may also affect 
      each other or interact during CXCL12-stimulated cellular responses. Altogether, 
      our results suggest that CXCR4 variants may have distinct functional roles that 
      warrant additional investigation and could contribute to future development of 
      novel drug interventions.
CI  - Copyright: (c) 2023 Park et al. This is an open access article distributed under 
      the terms of the Creative Commons Attribution License, which permits unrestricted 
      use, distribution, and reproduction in any medium, provided the original author 
      and source are credited.
FAU - Park, Hee-Kyung
AU  - Park HK
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Nguyen, Lan Phuong
AU  - Nguyen LP
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Nguyen, Thai Uy
AU  - Nguyen TU
AUID- ORCID: 0000-0002-4908-1185
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Cho, Minyeong
AU  - Cho M
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Nguyen, Huong Thi
AU  - Nguyen HT
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Hurh, Sunghoon
AU  - Hurh S
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Kim, Hong-Rae
AU  - Kim HR
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Seong, Jae Young
AU  - Seong JY
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Lee, Cheol Soon
AU  - Lee CS
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
FAU - Ham, Byung-Joo
AU  - Ham BJ
AD  - Department of Psychiatry, College of Medicine, Korea University, Seoul, Republic 
      of Korea.
FAU - Hwang, Jong-Ik
AU  - Hwang JI
AD  - Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 
      Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230504
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Ligands)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (CXCR4 protein, human)
SB  - IM
MH  - Humans
MH  - HEK293 Cells
MH  - Ligands
MH  - *Receptors, CXCR4/metabolism
MH  - *Chemokine CXCL12/genetics/metabolism
MH  - Signal Transduction
MH  - Protein Processing, Post-Translational
PMC - PMC10159351
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/05/04 18:42
MHDA- 2023/05/08 10:17
PMCR- 2023/05/04
CRDT- 2023/05/04 14:05
PHST- 2022/12/02 00:00 [received]
PHST- 2023/02/28 00:00 [accepted]
PHST- 2023/05/08 10:17 [medline]
PHST- 2023/05/04 18:42 [pubmed]
PHST- 2023/05/04 14:05 [entrez]
PHST- 2023/05/04 00:00 [pmc-release]
AID - PONE-D-22-33116 [pii]
AID - 10.1371/journal.pone.0283015 [doi]
PST - epublish
SO  - PLoS One. 2023 May 4;18(5):e0283015. doi: 10.1371/journal.pone.0283015. 
      eCollection 2023.