Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4

Eun Kyung Kwon, Chan Ki Min, Yuri Kim, Jae Won Lee, Abdimadiyeva Aigerim, Sebastian Schmidt, Hyun Jun Nam, Seong Kyu Han, Kuglae Kim, Jeong Seok Cha, Hoyoung Kim, Sanguk Kim, Hyun Soo Cho, Myung Sik Choi, Nam Hyuk Cho

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Abstract

Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRβ, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1864
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

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G-Protein-Coupled Receptors
T-Lymphocytes
Saimiriine Herpesvirus 2
Human Herpesvirus 8
Herpesviridae
T-Cell Antigen Receptor
Immune Evasion
Weapons
Chemokine Receptors
Human Herpesvirus 4
Immunoprecipitation
Small Interfering RNA
Ligation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Kwon, Eun Kyung ; Min, Chan Ki ; Kim, Yuri ; Lee, Jae Won ; Aigerim, Abdimadiyeva ; Schmidt, Sebastian ; Nam, Hyun Jun ; Han, Seong Kyu ; Kim, Kuglae ; Cha, Jeong Seok ; Kim, Hoyoung ; Kim, Sanguk ; Cho, Hyun Soo ; Choi, Myung Sik ; Cho, Nam Hyuk. / Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2017 ; Vol. 1864, No. 1. pp. 1-11.
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abstract = "Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRβ, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.",
author = "Kwon, {Eun Kyung} and Min, {Chan Ki} and Yuri Kim and Lee, {Jae Won} and Abdimadiyeva Aigerim and Sebastian Schmidt and Nam, {Hyun Jun} and Han, {Seong Kyu} and Kuglae Kim and Cha, {Jeong Seok} and Hoyoung Kim and Sanguk Kim and Cho, {Hyun Soo} and Choi, {Myung Sik} and Cho, {Nam Hyuk}",
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Kwon, EK, Min, CK, Kim, Y, Lee, JW, Aigerim, A, Schmidt, S, Nam, HJ, Han, SK, Kim, K, Cha, JS, Kim, H, Kim, S, Cho, HS, Choi, MS & Cho, NH 2017, 'Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4', Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1864, no. 1, pp. 1-11. https://doi.org/10.1016/j.bbamcr.2016.10.008

Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4. / Kwon, Eun Kyung; Min, Chan Ki; Kim, Yuri; Lee, Jae Won; Aigerim, Abdimadiyeva; Schmidt, Sebastian; Nam, Hyun Jun; Han, Seong Kyu; Kim, Kuglae; Cha, Jeong Seok; Kim, Hoyoung; Kim, Sanguk; Cho, Hyun Soo; Choi, Myung Sik; Cho, Nam Hyuk.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1864, No. 1, 01.01.2017, p. 1-11.

Research output: Contribution to journalArticle

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T1 - Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4

AU - Kwon, Eun Kyung

AU - Min, Chan Ki

AU - Kim, Yuri

AU - Lee, Jae Won

AU - Aigerim, Abdimadiyeva

AU - Schmidt, Sebastian

AU - Nam, Hyun Jun

AU - Han, Seong Kyu

AU - Kim, Kuglae

AU - Cha, Jeong Seok

AU - Kim, Hoyoung

AU - Kim, Sanguk

AU - Cho, Hyun Soo

AU - Choi, Myung Sik

AU - Cho, Nam Hyuk

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRβ, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.

AB - Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRβ, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.

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