IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection
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 a...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-06-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00435-22 |
| _version_ | 1811237384231059456 |
|---|---|
| author | Gloria Griffante Weronika Hewelt-Belka Camilla Albano Francesca Gugliesi Selina Pasquero Sergio Fernando Castillo Pacheco Greta Bajetto Paolo Ettore Porporato Erica Mina Marta Vallino Christian Krapp Martin Roelsgaard Jakobsen John Purdy Jens von Einem Santo Landolfo Valentina Dell’Oste Matteo Biolatti |
| author_facet | Gloria Griffante Weronika Hewelt-Belka Camilla Albano Francesca Gugliesi Selina Pasquero Sergio Fernando Castillo Pacheco Greta Bajetto Paolo Ettore Porporato Erica Mina Marta Vallino Christian Krapp Martin Roelsgaard Jakobsen John Purdy Jens von Einem Santo Landolfo Valentina Dell’Oste Matteo Biolatti |
| author_sort | Gloria Griffante |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:23:30Z |
| format | Article |
| id | doaj.art-b40fe9f446da4f5a9789a39792830e92 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-12T12:23:30Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-b40fe9f446da4f5a9789a39792830e922022-12-22T03:33:14ZengAmerican Society for MicrobiologymBio2150-75112022-06-0113310.1128/mbio.00435-22IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus InfectionGloria Griffante0Weronika Hewelt-Belka1Camilla Albano2Francesca Gugliesi3Selina Pasquero4Sergio Fernando Castillo Pacheco5Greta Bajetto6Paolo Ettore Porporato7Erica Mina8Marta Vallino9Christian Krapp10Martin Roelsgaard Jakobsen11John Purdy12Jens von Einem13Santo Landolfo14Valentina Dell’Oste15Matteo Biolatti16Department of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Gdańsk, PolandDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyInstitute for Sustainable Plant Protection, CNR, Turin, ItalyDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Immunobiology, University of Arizona, Tucson, Arizona, USAInstitute of Virology, Ulm University Medical Center, Ulm, GermanyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, ItalyABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.00435-22IFI16glucose and lipid metabolismhuman cytomegaloviruslipidomicsvirus-host interactions |
| spellingShingle | Gloria Griffante Weronika Hewelt-Belka Camilla Albano Francesca Gugliesi Selina Pasquero Sergio Fernando Castillo Pacheco Greta Bajetto Paolo Ettore Porporato Erica Mina Marta Vallino Christian Krapp Martin Roelsgaard Jakobsen John Purdy Jens von Einem Santo Landolfo Valentina Dell’Oste Matteo Biolatti IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection mBio IFI16 glucose and lipid metabolism human cytomegalovirus lipidomics virus-host interactions |
| title | IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection |
| title_full | IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection |
| title_fullStr | IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection |
| title_full_unstemmed | IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection |
| title_short | IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection |
| title_sort | ifi16 impacts metabolic reprogramming during human cytomegalovirus infection |
| topic | IFI16 glucose and lipid metabolism human cytomegalovirus lipidomics virus-host interactions |
| url | https://journals.asm.org/doi/10.1128/mbio.00435-22 |
| work_keys_str_mv | AT gloriagriffante ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT weronikaheweltbelka ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT camillaalbano ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT francescagugliesi ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT selinapasquero ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT sergiofernandocastillopacheco ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT gretabajetto ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT paoloettoreporporato ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT ericamina ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT martavallino ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT christiankrapp ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT martinroelsgaardjakobsen ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT johnpurdy ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT jensvoneinem ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT santolandolfo ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT valentinadelloste ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection AT matteobiolatti ifi16impactsmetabolicreprogrammingduringhumancytomegalovirusinfection |