Wang Qianruo, Zhao Jianqing, Zhang Mai, Sun Meixin, Fu Zhen F, Zhao Ling, Zhou Ming
National Key Laboratory of Agricultural Microbiology Huazhong Agricultural University, Wuhan, China.
Hubei Hongshan Laboratory, Wuhan, China.
J Virol. 2024 Dec 17;98(12):e0160724. doi: 10.1128/jvi.01607-24. Epub 2024 Nov 5.
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.
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.
脂滴（LDs）可与其他细胞器相互作用以调节细胞死亡，并且据报道其在病毒复制中也发挥重要作用。然而，脂滴、细胞死亡和病毒复制之间的相互作用仍不清楚。神经侵袭性病毒，如日本脑炎病毒（JEV）、狂犬病病毒（RABV）和脑心肌炎病毒（EMCV），仍然威胁着全球公共卫生并引起了广泛关注。在此，我们揭示神经侵袭性病毒感染通过上调二酰甘油O-酰基转移酶2（DGAT2）的表达来促进细胞甘油三酯生物合成，从而促进脂滴形成，并增加脂滴表面蛋白2（PLIN2）的表达，进而促进神经侵袭性病毒复制。此外，PLIN2可通过恢复线粒体电位并与抗凋亡蛋白Bcl-2（特别是136-209氨基酸区域）相互作用，降低Bcl-2第17位赖氨酸处K48连接的泛素化，从而中断BAX-Cytc-半胱天冬酶-3凋亡途径，减少线粒体损伤并抑制细胞凋亡。总之，我们阐明神经侵袭性病毒利用脂滴表面蛋白来限制受感染细胞的凋亡，为神经侵袭性病毒的发病机制和抗病毒治疗药物开发提供了新的见解。
神经侵袭性病毒是一种能够侵入并感染中枢神经系统，可能导致严重神经损伤和疾病的病原体，对公共卫生构成重大威胁。在此，我们发现神经侵袭性病毒可利用脂滴表面蛋白PLIN2促进病毒复制。值得注意的是，PLIN2可通过恢复线粒体电位并与抗凋亡蛋白Bcl-2（特别是136-209氨基酸区域）相互作用，降低Bcl-2第17位赖氨酸处K48连接的泛素化，从而中断BAX-Cytc-半胱天冬酶-3凋亡途径，减少线粒体损伤并抑制细胞凋亡。这项研究揭示了神经侵袭性病毒通过利用脂滴来避免受感染细胞凋亡的共同策略，这扩展了脂滴在病毒发病机制中的重要作用，并可能激发该领域的进一步研究。
