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J. Biol. Chem., Vol. 283, Issue 7, 3951-3959, February 15, 2008

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Activation of CXCR4 Triggers Ubiquitination and Down-regulation of Major Histocompatibility Complex Class I (MHC-I) on Epithelioid Carcinoma HeLa Cells^*

Ziqing Wang, Li Zhang, Aimin Qiao^¶||, Kurt Watson^¶||, Jingwu Zhang, and Guo-Huang Fan^¶||1

From the Institute of Health Sciences, Shanghai Institutes for Biological Sciences Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China, the ^¶Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212, the ^||Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, Tennessee 37208, and the Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37212

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.

Received for publication, August 16, 2007 , and in revised form, November 19, 2007.

^* This work was supported in part by a grant from Science and Technology Commission of Shanghai Municipality (project 04DZ14902), a Merit Award from the Dept. of Veterans (to G.-H. Fan), and a Specialized Neuroscience Research Program (SNRP) Grant (U54NS41071) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 615-327-6363; Fax: 615-327-6757; E-mail: gfan{at}mmc.edu.

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