Coxsackievirus B3 (CVB3) is the predominant pathogen of viral
myocarditis. In our previous study, we found that CVB3 caused abnormal
lipid accumulation in host cells. However, the underlying mechanisms by which CVB3 disrupts and exploits the host lipid metabolism are not well understood.
Sterol regulatory element binding protein 1 (SREBP1) is the major transcriptional factor in lipogenic genes expression. In this study, we demonstrated that CVB3
infection and nonstructural 2A
protein upregulated and activated SREBP1a at the transcriptional level. Deletion analysis of SREBP1a promoter revealed that two regions, -1821/-1490 and -312/+217, in this promoter were both required for its activation by 2A. These promoter regions possessed several binding motifs for
transcription factor SP1. Next, we used SP1-specific small interfering RNAs (siRNAs) to confirm that SP1 might be the essential factor in SREBP1a upregulation by 2A. Furthermore, we showed that MEK/ERK pathway was involved in the activation of SREBP1a by 2A and that blocking this signaling pathway with the specific inhibitor
U0126 attenuated SREBP1a activation and
lipid accumulation by 2A. Finally, we showed that inhibition of SREBP1 with siRNAs attenuated
lipid accumulation induced by CVB3
infection and reduced virus replication. Moreover, inhibition of the MEK/ERK pathway also led to reduction of SREBP1a activation,
lipid accumulation, and virus replication during CVB3
infection. Taken together, these data demonstrate that CVB3 nonstructural 2A
protein activates SREBP1a at the transcription level through a mechanism involving
MEK/ERK signaling pathway and
SP1 transcription factor, which promotes cellular
lipid accumulation and benefits virus replication.IMPORTANCE Coxsackievirus B3 (CVB3)
infection is the leading cause of viral
myocarditis, but effective
vaccines and
antiviral therapies against CVB3
infection are still lacking. It is important to understand the precise interactions between host and virus for the rational design of effective
therapies. During
infection, CVB3 disrupts and exploits host lipid metabolism to promote excessive
lipid accumulation, which benefits virus replication. SREBP1 is the master regulator of cellular lipid metabolism. Here, we report that one of the
viral nonstructural proteins, 2A, upregulates and activates SREBP1a. Furthermore, we find that inhibition of SREBP1 decreases CVB3 virus replication. These results reveal the regulation of SREBP1a expression by 2A and the roles of SREBP1 in
lipid accumulation and viral replication during CVB3
infection. Our findings provide a new insight into CVB3 host interactions and inform a potential novel therapeutic target for this important pathogen.