are employees of and own stock in BioAegis Therapeutics, Inc. which is developing recombinant human plasma gelsolin for potential clinical use. Other authors have declared that no conflict of interest exists.

Cdc42. 4,5 In our study, the doubly lipidated R186C Cdc42 mutant was retained in the Golgi (see Fig E4 , B). This impaired its plasma membrane anchoring and resulted in actin polymerization defects and hyperactivation of NF-kB signaling.In conclusion, our study identifies a strong link between impaired cytosol/membrane cycling of Cdc42 resulting from abnormal double lipidation, partial defects in actin polymerization, and hyperactivation of NF-kB signaling, which can explain the pathophysiology of the disease. More broadly, our findings are consistent with reports in the literature that link inflammation with actin turnover 6 and membrane targeting of Rho GTPases. [7][8][9] Thus, further investigation of the various consequences of CDC42 mutations are required because these mutations arise in a broad spectrum of clinical phenotypes. Ultimately, it offers the possibility of designing specific therapeutic targeting of this pathway that is newly involved in autoinflammatory diseases.

Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.