Human rhinovirus promotes STING trafficking to replication organelles to promote viral replication

Abstract

Human rhinovirus (HRV), like coronavirus (HCoV), are positive-strand RNA viruses that cause both upper and lower respiratory tract illness, with their replication facilitated by concentrating RNA-synthesizing machinery in intracellular compartments made of modified host membranes, referred to as replication organelles (ROs). Here we report a non-canonical, essential function for stimulator of interferon genes (STING) during HRV infections. While the canonical function of STING is to detect cytosolic DNA and activate inflammatory responses, HRV infection triggers the release of STIM1-bound STING in the ER by lowering Ca2+, thereby allowing STING to interact with phosphatidylinositol 4-phosphate (PI4P) and traffic to ROs to facilitates viral replication and transmission via autophagy. Our results thus hint a critical function of STING in HRV viral replication and transmission, with possible implications for other RO-mediated RNA viruses.

Bovine delta papillomavirus E5 oncoprotein negatively regulates the cGAS-STING signaling pathway in cattle in a spontaneous model of viral disease

“…Imbalances in intracellular trafficking routes may have profound effects on STING activity ( 57 ). Furthermore, aberrant trafficking of STING could explain why its canonical function and subsequent downstream signaling are compromised during viral infection ( 59 ).…”

Rhinoviruses usurp STING for replication

“…A second study from Gagliardi, Scull and co-workers 9 strengthened the evidence base for STING as a proviral factor by showing that STING is required for replication of RV-A and RV-C, but not RV-B, in human airway epithelial cells. Now, the study from Triantafilou et al 3 provides additional evidence for the role of STING in the RV lifecycle. The work supports a proviral role for STING in bronchial and airway epithelial cells.…”

“…Rhinovirus species A and C, but not species B, have previously been shown to rely on STING for replication. Reporting in Nature Communications, Triantafilou et al 3 show that STING is a proviral factor for all rhinoviruses (RVs) and how RVs redirect STING to support replication in bronchial and airway epithelial cells.…”

STING activation depends on ACBD3 and other phosphatidylinositol 4-phosphate-regulating proteins

“…Binding is partly driven by electrostatic interactions between the inositol head-group of PI4P and cationic residues in PH domains 37 . Recently, the purified C-terminal domain of STING was shown to bind PI4P lipids 38 . Although STING shows no homology to other known PI4P-binding domains, computational modelling of STING in an active conformation pointed to a patch of basic amino acids in close proximity to the transmembrane helices of STING that can accommodate PI4P 38 .…”

“…Recently, the purified C-terminal domain of STING was shown to bind PI4P lipids 38 . Although STING shows no homology to other known PI4P-binding domains, computational modelling of STING in an active conformation pointed to a patch of basic amino acids in close proximity to the transmembrane helices of STING that can accommodate PI4P 38 . Although more data is needed to confirm STING binding to PI4P in cells, such an interaction may regulate the duration of signalling by anchoring ligand-bound STING to the TGN.…”