IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection

mBio

Weronika Hewelt-Belka¹  Christian Krapp²  Martin Roelsgaard Jakobsen²  John Purdy³  Paolo Ettore Porporato⁴  Erica Mina⁴  Matteo Biolatti⁵  Camilla Albano⁵  Selina Pasquero⁵  Francesca Gugliesi⁵  Valentina Dell’Oste⁵  Sergio Fernando Castillo Pacheco⁵  Greta Bajetto⁵  Gloria Griffante⁵  Santo Landolfo⁵  Marta Vallino⁶  Jens von Einem⁷ 

[1] Department of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Gdańsk, Poland;Department of Biomedicine, Aarhus University, Aarhus, Denmark;Department of Immunobiology, University of Arizona, Tucson, Arizona, USA;Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy;Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy;Institute for Sustainable Plant Protection, CNR, Turin, Italy;Institute of Virology, Ulm University Medical Center, Ulm, Germany;

关键词: IFI16;    glucose and lipid metabolism;    human cytomegalovirus;    lipidomics;    virus-host interactions;   

DOI  :  10.1128/mbio.00435-22

来源: DOAJ

【 摘 要 】

ABSTRACT Cellular lipid metabolism plays a pivotal role in human cytomegalovirus (HCMV) infection, as increased lipogenesis in HCMV-infected cells favors the envelopment of newly synthesized viral particles. As all cells are equipped with restriction factors (RFs) able to exert a protective effect against invading pathogens, we asked whether a similar defense mechanism would also be in place to preserve the metabolic compartment from HCMV infection. Here, we show that gamma interferon (IFN-γ)-inducible protein 16 (IFI16), an RF able to block HCMV DNA synthesis, can also counteract HCMV-mediated metabolic reprogramming in infected primary human foreskin fibroblasts (HFFs), thereby limiting virion infectivity. Specifically, we find that IFI16 downregulates the transcriptional activation of the glucose transporter 4 (GLUT4) through cooperation with the carbohydrate-response element-binding protein (ChREBP), thereby reducing HCMV-induced transcription of lipogenic enzymes. The resulting decrease in glucose uptake and consumption leads to diminished lipid synthesis, which ultimately curbs the de novo formation of enveloped viral particles in infected HFFs. Consistently, untargeted lipidomic analysis shows enhanced cholesteryl ester levels in IFI16 KO versus wild-type (WT) HFFs. Overall, our data unveil a new role of IFI16 in the regulation of glucose and lipid metabolism upon HCMV replication and uncover new potential targets for the development of novel antiviral therapies. IMPORTANCE Human cytomegalovirus (HCMV) gathers all the substrates and enzymes necessary for the assembly of new virions from its host cell. For instance, HCMV is known to induce cellular metabolism of infected cells to favor virion assembly. Cells are, however, equipped with a first-line defense represented by restriction factors (RFs), which after sensing viral DNA can trigger innate and adaptive responses, thereby blocking HCMV replication. One such RF is IFN-γ-inducible protein 16 (IFI16), which we have shown to downregulate viral replication in human fibroblasts. Thus, we asked whether IFI16 would also play a role in preserving cellular metabolism upon HCMV infection. Our findings highlight an unprecedented role of IFI16 in opposing the metabolic changes elicited by HCMV, thus revealing new promising targets for antiviral therapy.

【 授权许可】

Unknown