S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
Constitutive activation of T cells by g2-herpesviral GPCR through the interaction with CXCR4
감마2-헤르페스 바이러스의 GPCR과 CXCR4의 상호작용에 의한 T세포의 활성화
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- Herpesviruses; vGPCR; Chemokine-receptor; Heterodimerization; T cell activation; Internalization
- 학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 조남혁.
- Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling to ensure successful infection and propagation. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). The open reading frame (ORF) 74 of γ2-herpesviruses encodes a G protein-coupled receptor which is highly conserved in members of this subfamily and is homologous to the CXCR2 chemokine receptor. In contrast to host chemokine receptors, which are activated in a ligand dependent manner and predominantly couple to Gi/o proteins, several vGPCRs are constitutively active and can couple to multiple G proteins. Even though vGPCRs modulate various cellular signaling pathways to 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, I report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ-herepesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4 in the absence of any cognate ligand. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposis sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus (EBV). 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 TCRβ and proximal T cell receptor (TCR) signaling molecules, such as 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.