Activation of CXCR4 Triggers Ubiquitination and Down-regulation of Major Histocompatibility Complex Class I (MHC-I) on Epithelioid Carcinoma HeLa Cells *
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 283, Issue: 7, Page: 3951-3959
2008
- 19Citations
- 41Captures
- 3Mentions
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Metrics Details
- Citations19
- Citation Indexes19
- 19
- CrossRef14
- Captures41
- Readers41
- 41
- Mentions3
- References3
- Wikipedia3
Article Description
Many cancer cells display down-regulated major histocompatibility complex (MHC) class I antigen (MHC-I), which seems to enable them to evade immune surveillance, whereas the underlying mechanisms remain incompletely understood. Here, we demonstrate that ligand (CXCL12) stimulation of CXCR4, a major chemokine receptor expressed in many malignant cancer cells, induced MHC-I heavy chain down-regulation from the cell surface of the human epithelioid carcinoma HeLa cells, the human U251 and U87 glioblastoma cells, the human MDA-MD 231 breast cancer cells, and the human SK-N-BE ( 2 ) neuroblastoma cells. Activation of CXCR4 also induced MHC-I down-regulation in human peripheral blood mononuclear cells. The internalized MHC-I heavy chain molecules were partially co-localized with Rab7, a later endosomal marker. Activation of CXCR4 induced ubiquitination of MHC-I heavy chain, and mutation of the C-terminal two lysine residues (Lys-332, Lys-337) on one of the MHC-I alleles, HLA.B7, blocked CXCR4-evoked ubiquitination and down-regulation of HLA.B7. Moreover, purified GST-conjugated CXCR4 C terminus directly associated with the purified His-tagged β2-microglobulin (β2M), and MHC-I heavy chain was co-immunoprecipitated with CXCR4 in a β2M-dependent manner. This interaction appears to be critical for CXCR4-evoked down-regulation of MHC-I heavy chain as evidenced by the data that MHC-I heavy chain down-regulation was inhibited by either truncation of the CXCR4 C terminus or knockdown of β2M. All together, these findings shed new light on the role of CXCR4 in tumor evasion of immune surveillance via inducing MHC-I down-regulation from the cell surface.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925820697046; http://dx.doi.org/10.1074/jbc.m706848200; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=42949157932&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/18083706; http://www.jbc.org/lookup/doi/10.1074/jbc.M706848200; https://syndication.highwire.org/content/doi/10.1074/jbc.M706848200; https://linkinghub.elsevier.com/retrieve/pii/S0021925820697046; https://dx.doi.org/10.1074/jbc.m706848200
American Society for Biochemistry & Molecular Biology (ASBMB)
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