How does the purine metabolic checkpoint FAMIN prevent immunopathology?

Children with Still's disease, the paradigm of autoinflammation-cum-autoimmunity, are predisposed to developing a cytokine storm with excessive activation of T lymphocytes upon viral infection. Loss-of-function of FAMIN is the sole known cause for monogenic Still's disease. We de-orphaned FAMIN as an unprecedented purine nucleoside enzyme that combines ADA-, PNP- and MTAP-like activities with adenosine phosphorolysis – challenging fundamental principles of purine metabolism. Dendritic cells with absent FAMIN activity prime for excess antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in exaggerated virus-specific T cell responses and immunopathology. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ~6.3% of mankind is homozygous, and which predisposes for Crohn's disease and leprosy. Here we will address FAMIN biology from virtually atomic to organismal resolution: We will explore how FAMIN operates in a cell, and how it controls energy metabolism, ascertaining redox and pH homeostasis. We will investigate how FAMIN in dendritic cells potently restrains T cell priming, and whether the FAMIN-coordinated biochemical mechanisms are involved in often fatal virus-induced cytokine release syndromes. This work will reveal an ancient biochemical mechanism that potently controls adaptive immune activation at a very fundamental level, providing insight into immunity to pathogens, autoinflammation and autoimmunity.