Sexual dimorphism is exhibited remarkably in the female predominance of autoimmune diseases (e.g. systemic lupus erythematosus, female‐to‐male ratio 9 : 1). To understand the female bias in autoimmunity, we focused on vestigial‐like family member 3 (VGLL3), a molecule with increased expression in females and known to promote autoimmunity. We report that VGLL3 mediates the cellular stress response by upregulating p53 and IL‐17C. Energy stress allows VGLL3 to be induced by IFNα, which ultimately leads to p53‐dependent, lupus‐associated, inflammatory cell death. Our results suggest that female‐biased expression of VGLL3 helps cells adapt to metabolic stress, which, intriguingly, is known as a significant challenge during the evolution of placental mammals due to the need to feed a developing embryo. The findings also uncover the importance of maintaining metabolic homeostasis in the prevention of autoimmunity.

中文翻译：

---

转录辅因子 VGLL3 的免疫代谢功能为自身免疫中的性别二态性提供了进化原理

性别二态性在自身免疫性疾病（例如系统性红斑狼疮，男女比例为 9:1）的女性占优势中表现出显着。为了了解自身免疫中的女性偏见，我们专注于退化样家族成员 3 (VGLL3)，这是一种在女性中表达增加且已知可促进自身免疫的分子。我们报告说 VGLL3 通过上调 p53 和 IL-17C 来介导细胞应激反应。能量压力允许 VGLL3 被 IFNα 诱导，最终导致 p53 依赖性、狼疮相关的炎症细胞死亡。我们的研究结果表明，VGLL3 的女性偏向表达有助于细胞适应代谢压力，有趣的是，由于需要喂养发育中的胚胎，这被认为是胎盘哺乳动物进化过程中的重大挑战。