Diacylglycerol O-acyltransferase 2, a novel target of flavivirus NS2B3 protease, promotes zika virus replication by regulating lipid droplet formation

Recently, researchers in Dr. Chao Liu and Dr. Ping Zhang's team of Sun Yat-sen University identified a novel target of flavivirus protease NS2B3—diacylglycerol O-acyltransferase 2 (DGAT2), a key rate-limiting enzyme catalyzing the final step of triglyceride biosynthesis, as a Zika virus (ZIKV) dependency factor.

It was revealed that DGAT2 is cleaved by ZIKV protease NS2B3, as a result, the stability of DGAT2 is enhanced, providing more stable support for viral replication. Furthermore, DGAT2 is recruited by NS proteins to the viral replication site, and functions as a tethering bridge between ER and lipid droplet (LD), regulating LD accumulation to supply energy for viral replication.

“So far, all reported cellular targets of flaviviral NS2B3 play antiviral roles, and the NS2B3-mediated cleavage generally destroy their integrity and enable virus to antagonize their functions,” said Dr. Chao Liu, an associate professor of Sun Yat-sen University at Zhongshan School of Medicine. “As far as we know, DGAT2 is the first proviral factor cleaved by flaviviral protease NS2B3.”

DGATs, encompassing DGAT1 and DGAT2, serve as the pivotal rate-limiting enzymes responsible for catalyzing the final step in triglyceride biosynthesis. In this study, they showed that DGAT2, but not DGAT1, is a proviral factor for ZIKV replication. Interestingly, DGAT1, rather than DGAT2, plays a proviral role in the replication of HCV and rabies virus.

“Structurally, DGAT1 and DGAT2 differ greatly as predicted by AlphaFold3,” said Dr. Ping Zhang, a professor of Sun Yat-sen University at Zhongshan School of Medicine. “Although DGAT1/DGAT2 plays an overlapping role in triglyceride biosynthesis, each of them has its unique functions.”

“Particularly, DGAT2, but not DGAT1, can tether between ER and LD via its LD targeting domain, allowing the channeling of triglycerides from ER to LD for the LD expansion,” Dr. Chao Liu said. “Different viruses may have different requirements for lipid metabolism.”

Further evidence needs to be provided to elucidate the mechanism of LD accumulation and expansion affected by DGAT2 upon ZIKV infection. The changes in ZIKV-induced LD components, such as lipid types, molecular contents, location movement, and surface proteins should be evaluated in the future.