Viperin regulates cellular lipid metabolism during human cytomegalovirus infection.
Human cytomegalovirus (HCMV) has been shown to induce increased lipogenesis in infected cells, and this is believed to be required for proper virion envelopment. We show here that this increase is a consequence of the virus-induced redistribution of the host protein viperin to mitochondria and its capacity to interact with and block the function of the mitochondrial trifunctional protein (TFP), the enzyme that mediates fatty acid-β-oxidation. The resulting decrease in cellular ATP levels activates the enzyme AMP-activated protein kinase (AMPK), which induces expression of the glucose transporter GLUT4, resulting in increased glucose import and translocation to the nucleus of the glucose-regulated transcription factor ChREBP. This induces increased transcription of genes encoding lipogenic enzymes, increased lipid synthesis and lipid droplet accumulation, and generation of the viral envelope. Viperin-dependent lipogenesis is required for optimal production of infectious virus. We show that all of these metabolic outcomes can be replicated by direct targeting of viperin to mitochondria in the absence of HCMV infection, and that the motif responsible for Fe-S cluster binding by viperin is essential. The data indicate that viperin is the major effector underlying the ability of HCMV to regulate cellular lipid metabolism.
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Jun-Young
JY
Seo
Peter
P
Cresswell
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000821:virology; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000090123:Viperin Protein
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D051275:Glucose Transporter Type 4; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; C417529:Rsad2 protein, mouse; D000090123:Viperin Protein; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C444427:RSAD2 protein, human