Activation of cytomegalovirus-encoded G protein-coupled receptor UL33 by an innate N-terminal peptide

TL;DR

This study reveals how a virus uses a built-in peptide to activate a receptor, altering host cell signaling to aid its replication.

Contribution

The study identifies the N-terminal peptide of UL33 as a self-agonist that activates the receptor in a non-canonical manner.

Findings

The N-terminal peptide of UL33 acts as a tethered self-agonist, inducing a non-canonical active state.

Structure-guided mutagenesis confirms the N-terminus is essential for G protein-mediated signaling.

The mechanism allows HCMV to hijack and modulate host G protein signaling pathways.

Abstract

Human cytomegalovirus (HCMV) encodes the orphan G protein-coupled receptor (GPCR) UL33, which exhibits constitutive activity that disrupts host G protein signalling, facilitating efficient viral replication and pathogenesis. The cryo-electron microscopy (cryo-EM) structure of UL33 bound to the Gs subtype of G protein reveals the N-terminal peptide as a tethered ligand reminiscent of the protease-activated receptors and adhesion GPCRs. This self-agonism induces a non-canonical active state that facilitates promiscuous G protein coupling, a plausible viral strategy for fine-tuning host signalling. Structure-guided mutagenesis disrupting key interactions between the N-terminus and its binding pocket abolishes G protein-mediated signalling, confirming the role of the N-terminus as a self-agonist. Our findings elucidate the structural basis for this activation mechanism and highlight the strategies employed by HCMV to hijack host G protein signalling.

Drzazga et al. report that the HCMV-GPCR UL33 uses its N-terminal peptide as a tethered self-agonist to induce a non-canonical active state enabling broad G protein coupling. Structure-guided mutagenesis and cryo-EM analysis reveal the mechanistic basis of this self-activation, highlighting how HCMV may fine-tune and hijack host signalling pathways.

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