Patterns of Human and Porcine Gammaherpesvirus-encoded BILF1 Receptor Endocytosis

Overview

Journal Cell Mol Biol Lett

Publisher Biomed Central

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2023 Feb 22

PMID 36810008

Authors

Masa Mavri

Sanja Glisic

Milan Sencanski

Milka Vrecl

Mette M Rosenkilde

Katja Spiess

Valentina Kubale

Affiliations

Soon will be listed here.

Abstract

Background: The viral G-protein-coupled receptor (vGPCR) BILF1 encoded by the Epstein-Barr virus (EBV) is an oncogene and immunoevasin and can downregulate MHC-I molecules at the surface of infected cells. MHC-I downregulation, which presumably occurs through co-internalization with EBV-BILF1, is preserved among BILF1 receptors, including the three BILF1 orthologs encoded by porcine lymphotropic herpesviruses (PLHV BILFs). This study aimed to understand the detailed mechanisms of BILF1 receptor constitutive internalization, to explore the translational potential of PLHV BILFs compared with EBV-BILF1.

Methods: A novel real-time fluorescence resonance energy transfer (FRET)-based internalization assay combined with dominant-negative variants of dynamin-1 (Dyn K44A) and the chemical clathrin inhibitor Pitstop2 in HEK-293A cells was used to study the effect of specific endocytic proteins on BILF1 internalization. Bioluminescence resonance energy transfer (BRET)-saturation analysis was used to study BILF1 receptor interaction with β-arrestin2 and Rab7. In addition, a bioinformatics approach informational spectrum method (ISM) was used to investigate the interaction affinity of BILF1 receptors with β-arrestin2, AP-2, and caveolin-1.

Results: We identified dynamin-dependent, clathrin-mediated constitutive endocytosis for all BILF1 receptors. The observed interaction affinity between BILF1 receptors and caveolin-1 and the decreased internalization in the presence of a dominant-negative variant of caveolin-1 (Cav S80E) indicated the involvement of caveolin-1 in BILF1 trafficking. Furthermore, after BILF1 internalization from the plasma membrane, both the recycling and degradation pathways are proposed for BILF1 receptors.

Conclusions: The similarity in the internalization mechanisms observed for EBV-BILF1 and PLHV1-2 BILF1 provide a foundation for further studies exploring a possible translational potential for PLHVs, as proposed previously, and provides new information about receptor trafficking.

Citing Articles

Third intracellular loop of HCMV US28 is necessary for signaling and viral reactivation.

Medica S, Denton M, Diggins N, Kramer-Hansen O, Crawford L, Mayo A J Virol. 2024; 99(1):e0180124.

PMID: 39655954 PMC: 11784217. DOI: 10.1128/jvi.01801-24.

Correction: Patterns of human and porcine gammaherpesvirus-encoded BILF1 receptor endocytosis.

Mavri M, Glisic S, Sencanski M, Vrecl M, Rosenkilde M, Spiess K Cell Mol Biol Lett. 2023; 28(1):94.

PMID: 38001445 PMC: 10668409. DOI: 10.1186/s11658-023-00512-2.

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