Roles Of Cyclic GMP-AMP Synthase In Lupus-like Autoimmunity And Progeria

The presence of DNA in the cytosol is known to trigger robust innate immunity.Cyclic GMP-AMP（cGAMP）synthase（cGAS）is a cytosolic DNA sensor which can be activated by DNA irrespective of its sequence or origin to catalyze the synthesis of cGAMP.cGAMP functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines.Here we show that cGAS plays essential roles in autoimmunity and progeria caused by self-DNA.TREX1 encodes a major cellular DNA exonuclease.Mutations of this gene inhuman cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome（AGS）,familial chilblain lupus（FCL）and systemic lupus erythematosus（SLE）.Missense mutations in TREX1 have been considered as a main cause of autoimmune diseases.We created a lupus mouse model by engineering a D18N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders.The Trex1^D18N/D18N18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human FCL and SLE.Importantly,ablation of cGas gene in the Trex1^D18N/D18N18N/D18N mice rescued the lethality and all detectable pathological phenotypes,including multi-organ inflammation,interferon stimulated gene induction,autoantibody production and aberrant T-cell activation.These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function,providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.cGAS is essential for the cell senescence phenotypes.Hutchinson-GilfordProgeria Syndrome（HGPS）is a rare and devastating genetic disease caused by lamin A gene mutations.Zmpste24 is an essential metalloproteinase involved in the maturation of lamin A（Lmna）.A permanently farnesylated,toxic form of prelamin A accumulation was caused by Zmpste24 deficiency,which further disrupted the nuclear shape and chromatin organization,leading to DNA-damage accumulation and senescence.To better understand how HGPS phenotypes were caused by lamin A deficiency,we created a Zmpste24-deficient mouse model,which recapitulate many progeroid features of HGPS,including growth impairment,body weight loss,lipodystrophy,lipsotrichia and tissue functional defects.cGAS depletion significantly improves these progeroid features.Depletion of cGas reduces H3K9me3 levels,restores DNA repair capacity and delays senescence in progeroid cells.Moreover,depletion of cGas reduces the production of SASP and defers cell senescence in Zmpste24^-/-mice.These data suggest an essential role of cGAS in the pathogenesis of HGPS and support a potential therapeutic strategy for progeria by targeting cGAS.