Immunometabolic function of 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 VGLL3 (Vestigial-like-family-member 3), a female-increased molecule known to promote autoimmunity. We report that VGLL3 mediates 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 for the need to feed a developing embryo. It uncovers the importance of maintaining metabolic homeostasis in the prevention of autoimmunity.