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Receptor 2 High-Affinity Ligand for CC Chemokine Chemoattractant

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Receptor 2 High-Affinity Ligand for CC Chemokine Chemoattractant PC3-Secreted Microprotein Is a Novel Chemoattractant Protein and Functions as a High-Affinity Ligand for CC Chemokine Receptor 2 This information is current as of September 28, 2021. Xiaolei Pei, Qianying Sun, Yan Zhang, Pingzhang Wang, Xinjian Peng, Changyuan Guo, Enquan Xu, Yi Zheng, Xiaoning Mo, Jing Ma, Dixin Chen, Yang Zhang, Yingmei Zhang, Quansheng Song, Shuai Guo, Taiping Shi, Zhixin Zhang, Dalong Ma and Ying Wang Downloaded from J Immunol published online 17 January 2014 http://www.jimmunol.org/content/early/2014/01/17/jimmun ol.1300758 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 17, 2014, doi:10.4049/jimmunol.1300758 The Journal of Immunology PC3-Secreted Microprotein Is a Novel Chemoattractant Protein and Functions as a High-Affinity Ligand for CC Chemokine Receptor 2 Xiaolei Pei,*,1 Qianying Sun,*,1 Yan Zhang,*,1 Pingzhang Wang,*,†,‡ Xinjian Peng,* Changyuan Guo,* Enquan Xu,* Yi Zheng,* Xiaoning Mo,* Jing Ma,* Dixin Chen,* Yang Zhang,* Yingmei Zhang,*,† Quansheng Song,*,† Shuai Guo,‡ Taiping Shi,‡ Zhixin Zhang,x Dalong Ma,*,† and Ying Wang*,† PC3-secreted microprotein (PSMP) or microseminoprotein is a newly discovered secreted protein whose function is currently un- known. In this study, PSMP was found to possess chemotactic ability toward monocytes and lymphocytes, and its functional receptor Downloaded from was identified as CCR2B. PSMP was identified as a chemoattractant protein from a PBMC chemoattractant platform screen that we established. The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B- expressing THP-1 cells, but not peripheral blood neutrophils, even though it does not contain the classical structure of chemokines. CCR2B was identified as one receptor for PSMP-mediated chemotaxis by screening HEK293 cells that transiently expressed clas- sical chemokine receptors; results obtained from the chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays all confirmed this finding. To further identify the major function of PSMP, we analyzed its expression profile in tissues. PSMP http://www.jimmunol.org/ is highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue. In response to PSMP stimulation, phosphorylated ERK levels downstream of CCR2B signaling were upregulated in the PC3 cell line. Taken together, our data collectively suggest that PSMP is a chemoattractant protein acting as a novel CCR2 ligand that may influence inflammation and cancer development. The Journal of Immunology, 2014, 192: 000–000. hemoattractant cytokines or chemokines constitute a family mation (3, 4), cancer development (5, 6), and cardiovascular disease of structurally related proteins (1). Chemokines are divided (7, 8). into four major subfamilies, CC, CXC, CX3C, and XC, Members of the “chemokine-like function” (CLF) group cannot C by guest on September 28, 2021 based on the arrangement of their first two N-terminal cysteine res- be classified into known chemokine subfamilies but do share some idues. The first two cysteine residues can be adjacent to each other structural or functional features with classical chemokines and can (CC), contain a single amino acid (CXC) between them, contain signal through chemokine receptors. Several CLF chemokines that three random amino acids (CX3C) between them, or lack the first bind and activate chemokine receptors have been identified, such cysteine residue (XC). Chemokines can mediate their activities as MIF (9), b-defensins (10), and a tyrosyl-tRNA-synthetase frag- through G-protein–coupled receptors having a characteristic seven- ment (11), among others. transmembrane structure and transduce their signals to the inside Our laboratory focuses on finding new human gene encoding of the cell through heterotrimeric G-proteins (2). The chemokine proteins that have potential chemokine or CLF. After the com- superfamily plays an important role in acute and chronic inflam- pletion of the Human Genome Project, we established a database containing potential cytokines that includes 212 candidate genes, none of which have any currently reported function, immune re- *Department of Immunology, School of Basic Medical Sciences, and Key Laboratory lated or otherwise. We used a PBMC chemoattractant platform to of Medical Immunology of Ministry of Health, Peking University Health Science Center, Beijing 100191, China; †Center for Human Disease Genomics, Peking Uni- identify candidate chemoattractant cytokines and found that PC3- versity, Beijing 100191, China; ‡Chinese National Human Genome Center, Beijing secreted microprotein (PSMP), or microseminoprotein (MSMP) x 100176, China; and Beijing Red Cross Blood Center, Beijing 100088, China (12), a gene whose function is currently unknown, exhibited che- 1X. Pei, Q. Sun, and Yan Zhang contributed equally to this work. motaxis toward PBMCs. Received for publication March 20, 2013. Accepted for publication December 5, PSMP, or MSMP, homologous to b-microseminoprotein, is pre- 2013. dicted to be a secreted protein containing a signal peptide sequence This work was supported by the National Key Basic Research Program of China without the classical structure of chemokines. This protein is (Grant 2012CB518002), the National Natural Science Foundation of China (Grants 31270915 and 81071749), and the National Key New Drug Creation Program of strongly and with relative specificity expressed in the hormone- China (Grant 2009ZX09503-004). insensitive PC3 prostate cancer cell line and is also expressed in Address correspondence and reprint requests to Dr. Ying Wang, Peking University human prostate cancer (12). However, its function remains un- Health Science Center, 38 Xueyuan Road, Beijing 100191, China. E-mail address: known. In this article, we demonstrate that mature, secreted PSMP [email protected] could induce migration of human peripheral blood monocytes Abbreviations used in this article: ATCC, American Type Culture Collection; BFA, brefeldin A; BPH, benign prostatic hyperplasia; CLF, chemokine-like function; (PBMs), PBLs, and the human monocytic leukemia THP-1 cell line. MSMP, microseminoprotein; PBM, peripheral blood monocyte; PBST, PBS contain- The chemoattractant receptor for PSMP was determined to be ing 0.05% Tween 20; PMN, polymorphonuclear neutrophil; PSMP, PC3-secreted CCR2B through functionally screening the classical chemokine microprotein; PTX, pertussis toxin. receptors. Furthermore, PSMP may function in inflammation and Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 cancer development, as PSMP was highly expressed in both benign www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300758 2 PSMP IS A NOVEL HIGH-AFFINITY LIGAND FOR CCR2 prostatic hyperplasia (BPH) and some prostate cancers, and could chambers for 3 or 4 h. PBMs and PBLs that migrated into lower chambers be detected in breast tumor tissues. were counted as above. The chemotactic index was calculated from the mi- grated cell numbers after PSMP treatment, compared with the media-only control. Significant chemotaxis was defined as a chemotactic index . 2.0. Materials and Methods Chemotaxis assay of receptor-transfected HEK293 cells Materials, reagents, and chemicals HEK293 cells (ATCC) were cultured according to ATCC recommendations. RPMI 1640 medium and FBS were purchased from Life Technologies. Chemokine receptor expression plasmid (10 mg) was transiently transfected DMEM, brefeldin A (BFA), BSA, and anti-ERK1/2 were purchased from into HEK293 by electroporation at 120 V for 20 ms, using an electric pulse Sigma-Aldrich. Pertussis toxin (PTX) was purchased from Alexis Bio- generator (Electro Square Porator ECM 830; BTX, San Diego, CA). The 125 chemical. INa was obtained from DuPont. CXCL8, CXCL12, CCL2, chemotaxis assay was performed 48 h later using a 48-well microche- CCL5, and CCL8 were purchased from PeproTech. Fluo-3 AM was ob- motaxis chamber (Neuro probe). Cells that migrated to the lower part of tained from Invitrogen. PE goat anti-mouse IgG was purchased from Bio- the filter were fixed and stained with the Three Step Stain Set (Richard- Legend. Mouse anti-CCR2, RS102895, and anti–phospho-ERK (pTEpY) Allan Scientific); cells were counted in five randomly selected high-power were obtained from R&D Systems. The pcDB-CCR2B and pcDB-CCR5 fields (3400) per well. plasmids were constructed in our laboratory. CCR1, CCR3, and CCR8 ex- pression plasmids were kindly provided by Dr. Philip M. Murphy (Labora- Calcium flux assay tory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD). CCR2A and CCR2B After
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