Neuroinvasive virus utilizes a lipid droplet surface protein, perilipin2, to restrict apoptosis by decreasing Bcl-2 ubiquitination.

Abstract

Lipid droplets (LDs) can interact with other organelles to regulate cell death, and it has also been reported to play an important role in virus replication. However, the interplay among LDs, cell death, and viral replication remains unclear. Neuroinvasive viruses, such as Japanese encephalitis virus (JEV), rabies virus (RABV), and encephalomyocarditis virus (EMCV) still threaten global public health and raise intensive concerns. Here, we reveal that neuroinvasive virus infection enhances cellular triglyceride biosynthesis by upregulating the expression of diacylglycerol O-acyltransferase 2 (DGAT2) to promote LD formation and increase the expression of Perilipin 2 (PLIN2), an LD surface protein, which consequently facilitates neuroinvasive virus replication. Furthermore, PLIN2 could reduce mitochondrial damage and suppress apoptosis by restoring mitochondrial potential and interacting with anti-apoptotic protein Bcl-2, specifically the 136-209 amino acid region, to interrupt the BAX-Cytc-caspase-3 apoptotic pathway by decreasing the K48-linked ubiquitination of Bcl-2 at the 17th lysine. Together, we elucidate that neuroinvasive virus utilizes an LD surface protein to restrict the apoptosis of infected cells, providing a fresh insight into the pathogenesis and antiviral therapeutics development of neuroinvasive viruses.

Importance: The neuroinvasive virus is a kind of pathogen that is capable of infiltrating and infecting the central nervous system to potentially induce severe neurological damage and disorders, which pose a significant threat to public health. Here, we found that neuroinvasive viruses can utilize an LD surface protein PLIN2 to facilitate viral replication. Notably, PLIN2 could reduce mitochondrial damage and suppress apoptosis by restoring mitochondrial potential and interacting with anti-apoptotic protein Bcl-2, specifically the 136-209 amino acid region, to interrupt the BAX-Cytc-caspase-3 apoptotic pathway by decreasing the K48-linked ubiquitination of Bcl-2 at the 17th lysine. This study reveals a common strategy for neuroinvasive viruses to avoid apoptosis of infected cells by employing LDs, which extends the important role of LDs in viral pathogenesis and may inspire further research in this field.