Bonglack Emmanuela N, Hill Kaeden K, Barry Ashley P, Bartlett Alexandria, Castellano-Escuder Pol, Hirschey Matthew D, Luftig Micah A
Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
PLoS Pathog. 2025 May 22;21(5):e1012685. doi: 10.1371/journal.ppat.1012685. eCollection 2025 May.
Epstein-Barr virus (EBV) is a gamma herpesvirus that infects up to 95% of the human population by adulthood, typically remaining latent in the host memory B cell pool. In immunocompromised individuals, EBV can drive the transformation and rapid proliferation of infected B cells, ultimately resulting in neoplasia. The same transformation process can be induced in vitro, with EBV-infected peripheral blood B cells forming immortalized lymphoblastoid cell lines (LCLs) within weeks. In this study, we found that the fatty acid desaturases stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) are upregulated by EBV and crucial for EBV-induced B cell proliferation. We show that pharmacological and genetic inhibition of both SCD1 and FADS2 results in a significantly greater reduction in proliferation and cell cycle arrest, compared to perturbing either enzyme individually. Additionally, we found that inhibiting either SCD1 or FADS2 alone hypersensitizes LCLs to palmitate-induced apoptosis. Further free fatty acid profiling and metabolic analysis of dual SCD1/FADS2-inhibited LCLs revealed an increase in free unsaturated fatty acids, a reduction of oxidative phosphorylation, and a reduction of glycolysis, thereby linking the activity of SCD1 and FADS2 to overall growth-promoting metabolism. Lastly, we show that SCD1 and FADS2 are important in the growth of clinically derived EBV+ immunoblastic lymphoma cells. Collectively, these data demonstrate a previously uncharacterized role of lipid desaturation in EBV+ transformed B cell proliferation, revealing a metabolic pathway that can be targeted in future anti-lymphoma therapies.
爱泼斯坦-巴尔病毒（EBV）是一种γ疱疹病毒，到成年时，它感染高达95%的人类，通常潜伏在宿主记忆B细胞库中。在免疫功能低下的个体中，EBV可驱动受感染B细胞的转化和快速增殖，最终导致肿瘤形成。同样的转化过程也可在体外诱导，EBV感染的外周血B细胞在数周内形成永生化的淋巴母细胞系（LCLs）。在本研究中，我们发现脂肪酸去饱和酶硬脂酰辅酶A去饱和酶1（SCD1）和脂肪酸去饱和酶2（FADS2）被EBV上调，并且对EBV诱导的B细胞增殖至关重要。我们表明，与单独干扰任何一种酶相比，对SCD1和FADS2进行药理和基因抑制会导致增殖的显著更大程度降低和细胞周期停滞。此外，我们发现单独抑制SCD1或FADS2会使LCLs对棕榈酸诱导的凋亡高度敏感。对双重SCD1/FADS2抑制的LCLs进行进一步的游离脂肪酸谱分析和代谢分析发现，游离不饱和脂肪酸增加，氧化磷酸化减少，糖酵解减少，从而将SCD1和FADS2的活性与促进生长的整体代谢联系起来。最后，我们表明SCD1和FADS2在临床来源的EBV+免疫母细胞淋巴瘤细胞的生长中很重要。总体而言，这些数据证明了脂质去饱和在EBV+转化的B细胞增殖中以前未被表征的作用，揭示了一条可在未来抗淋巴瘤治疗中靶向的代谢途径。
