Viral G Protein–Coupled Receptors Encoded by β- and γ-Herpesviruses

Abstract

Herpesviruses are ancient large DNA viruses that have exploited gene capture as part of their strategy to escape immune surveillance, promote virus spreading, or reprogram host cells to benefit their survival. Most acquired genes are transmembrane proteins and cytokines, such as viral G protein–coupled receptors (vGPCRs), chemokines, and chemokine-binding proteins. This review focuses on the vGPCRs encoded by the human β- and γ-herpesviruses. These include receptors from human cytomegalovirus, which encodes four vGPCRs: US27, US28, UL33, and UL78; human herpesvirus 6 and 7 with two receptors: U12 and U51; Epstein-Barr virus with one: BILF1; and Kaposi's sarcoma-associated herpesvirus with one: open reading frame 74. We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from endogenous receptors. Finally, we briefly discuss the therapeutic targeting of vGPCRs as future treatment of acute and chronic herpesvirus infections. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Structural basis for constitutive activation and CXCL1 recognition of human herpesvirus 8-encoded G protein-coupled receptor KSHV-GPCR

“…US28 has a TM pocket for binding of CC chemokines of the MIP and MCP classes, and of CX3CL1 in a different mode (Rosenkilde et al, 2022). Still, the two-site model applies to these interactions between the receptor and its various ligands.…”

Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges

“…The G protein-coupled receptor (GPCR) family comprises a vast number of receptors, which are involved in diverse aspects of cell signaling in the body. Some viruses encode homologs of GPCRs, including viral chemokine receptors (vCKRs), with distinct roles in infection, cardiovascular disease, and various types of cancers ( 1 ). The herpesvirus family is particularly adept at chemokine mimicry with several members carrying and maintaining viral chemokines, receptors, and chemokine-binding proteins ( 2 ).…”

“…Often more than one structure for each receptor is defined, thereby capturing the receptors in various conformational states ( 35 , 36 ). For US28, an apo-structure as well as complexes with CX 3 CL1 and a G protein-biased CX 3 CL1 variant have been solved ( 1 , 32 – 34 ). Together, these have shed light on helical connectivity and the role of various receptor domains and microswitches for US28 activity.…”

“…Together, these have shed light on helical connectivity and the role of various receptor domains and microswitches for US28 activity. Overall, the structural alterations result in a differentiation of US28 from its homologous endogenous chemokine receptors (CX 3 CR1 and CCR1, CCR2, and CCR5) in terms of i) a broader chemokine recognition pattern ( 26 , 37 – 39 ); ii) a broader activation profile, not only including Gαi like the endogenous receptors, but also other G proteins such as Gαq ( 40 , 41 ); iii) a fast and constitutive internalization ( 24 , 27 , 28 , 42 , 43 ); and iv) a robust ligand-independent signaling ( 1 , 44 ).…”

“…From a structural point of view, US28 overall resembles other class A GPCRs (1,(32)(33)(34). Of note, recent years' advancements in structural biology of membrane proteins using for instance cryo-EM, have resulted in a multitude of structures across class A (and class B1) GPCRs.…”