IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection.
IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection.
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DOI：
10.1128/mbio.00435-22
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发表时间：
2022-06-28
期刊：
影响因子：
6.4
通讯作者：
Biolatti, Matteo
中科院分区：
文献类型：
--
作者：
Griffante, Gloria;Hewelt-Belka, Weronika;Albano, Camilla;Gugliesi, Francesca;Pasquero, Selina;Castillo Pacheco, Sergio Fernando;Bajetto, Greta;Porporato, Paolo Ettore;Mina, Erica;Vallino, Marta;Krapp, Christian;Jakobsen, Martin Roelsgaard;Purdy, John;von Einem, Jens;Landolfo, Santo;Dell'Oste, Valentina;Biolatti, Matteo
细胞脂质代谢在人巨细胞病毒（HCMV）感染中起着关键作用，因为HCMV感染细胞中脂肪生成的增加有利于新合成的病毒颗粒的消除。由于所有细胞都配备有能够对入侵病原体发挥保护作用的限制因子（RF），我们询问是否也存在类似的防御机制以保护代谢区室免受HCMV感染。在这里，我们发现γ干扰素（IFN-γ）诱导蛋白16（IFI 16），一种能够阻断HCMV DNA合成的RF，也可以抵消感染的原代人包皮成纤维细胞（HFF）中HCMV介导的代谢重编程，从而限制病毒体的感染性。具体来说，我们发现IFI 16下调转录激活的葡萄糖转运蛋白4（GLUT 4）通过合作与碳水化合物反应元件结合蛋白（ChREBP），从而减少HCMV诱导的脂肪生成酶的转录。由此导致的葡萄糖摄取和消耗的减少导致脂质合成减少，这最终抑制了感染的HFF中包膜病毒颗粒的从头形成。一致地，非靶向脂质组学分析显示IFI 16 KO相对于野生型（WT）HFF中胆固醇酯水平增强。总的来说，我们的数据揭示了IFI 16在HCMV复制后调节葡萄糖和脂质代谢中的新作用，并发现了开发新型抗病毒疗法的新的潜在靶点。
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.
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影响因子：
6.7
作者：
De Meo S;Dell'Oste V;Molfetta R;Tassinari V;Lotti LV;Vespa S;Pignoloni B;Covino DA;Fantuzzi L;Bona R;Zingoni A;Nardone I;Biolatti M;Coscia A;Paolini R;Benkirane M;Edfors F;Sandalova T;Achour A;Hiscott J;Landolfo S;Santoni A;Cerboni C
通讯作者：
Cerboni C
影响因子：
5.4
作者：
Biolatti, Matteo;Dell'Oste, Valentina;Landolfo, Santo
通讯作者：
Landolfo, Santo
影响因子：
4.8
作者：
Dalen, KT;Ulven, SM;Nebb, HI
通讯作者：
Nebb, HI
影响因子：
5.4
作者：
Fish, KN;Soderberg-Naucler, C;Nelson, JA
通讯作者：
Nelson, JA
影响因子：
5.3
作者：
Hsich, E;Zhou, YF;Epstein, SE
通讯作者：
Epstein, SE