Immunometabolic Function Of The Transcription Cofactor Vgll3 Provides An Evolutionary Rationale For Sexual Dimorphism In Autoimmunity

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 IFN alpha, 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.