Title: Human Cytomegalovirus Infection Induces Adipocyte-Like Lipogenesis through Activation of Sterol Regulatory Element Binding Protein 1
Abstract: Sterol regulatory element binding proteins (SREBPs) are essential transcriptional factors that control expression of lipogenic genes and adipocyte differentiation. Human cytomegalovirus (HCMV) infection has been shown to require the induction of lipogenesis. Here we show that the induction of lipogenesis and expression of key lipogenic enzymes in human fibroblasts occurs by 24 h post-HCMV infection. This activation correlates with increased cleavage of the SREBP1 precursors to form the mature active transcription factors that enter the nucleus to transcriptionally activate lipogenic genes. SREBP1 cleavage is normally inhibited by increased sterol levels; however, our data show that this level of control is overridden in infected cells to allow constitutive activation of lipogenesis. This process requires viral protein synthesis, since UV-irradiated HCMV cannot activate SREBP cleavage. The cleavage of SREBP1 requires it to be in complex with SREBP cleavage activation protein (SCAP). Depleting SCAP using short hairpin RNA (shRNA) showed that SREBP1 cleavage and the induction of lipogenic genes and lipid synthesis are all inhibited in HCMV-infected cells. As a result, production of infectious virions is reduced in SCAP-depleted cells. Thus, the SCAP-mediated mechanism for SREBP cleavage is utilized by HCMV during infection. Our studies suggest that HCMV induces adipocyte-like lipogenesis and overrides normal sterol feedback controls in order to maintain high levels of constitutive lipid synthesis during infection.