Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells.
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 beta2-microglobulin (beta2M), and MHC-I heavy chain was co-immunoprecipitated with CXCR4 in a beta2M-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 beta2M. 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.
Wang
Ziqing
Z
Institute of Health Sciences, Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Zhang
Li
L
Qiao
Aimin
A
Watson
Kurt
K
Zhang
Jingwu
J
Fan
Guo-Huang
GH
D018450:Disease Progression; D015536:Down-Regulation; D006367:HeLa Cells / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D019718:Receptors, CXCR4 / Q000378:metabolism* / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*
C527276:CXCR4 protein, human; D015395:Histocompatibility Antigens Class I; D019718:Receptors, CXCR4; D025801:Ubiquitin