Abstract
Cyropyrin-associated periodic syndromes (CAPS) are clinically distinct syndromes that encompass a phenotypic spectrum yet are caused by alterations in the same gene, NLRP3. Many CAPS cases and other NLRP3-autoinflammatory diseases (NLRP3-AIDs) are directly attributed to protein-coding alterations in NLRP3 and the subsequent dysregulation of the NLRP3 inflammasome leading to IL-1β-mediated inflammatory states. Here, we used bioinformatics tools, computational modeling, and computational assessments to explore the proteomic consequences of NLRP3 mutations, which potentially drive NLRP3 inflammasome dysregulation. We analyzed 177 mutations derived from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and the non-hereditary chronic infantile neurologic cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease (CINCA/NOMID), as well as other NLRP3-AIDs. We found an inverse relationship between clinical severity and the severity of predicted structure changes resulting from mutations in NLRP3. Bioinformatics tools and computational modeling revealed that NLRP3 mutations that are predicted to be structurally severely-disruptive localize around the ATP binding pocket and that specific proteo-structural changes to the ATP binding pocket lead to enhanced ATP binding affinity by altering hydrogen-bond and charge interactions. Furthermore, we demonstrated that NLRP3 mutations that are predicted to be structurally mildly- or moderately-disruptive affect protein-protein interactions, such as NLRP3-ASC binding and NLRP3-NLRP3 multimerization, enhancing inflammasome formation and complex stability. Taken together, we provide evidence that proteo-structural mechanisms can explain multiple mechanisms of inflammasome activation in NLRP3-AID.
Highlights
Inflammasomopathies, types of autoinflammatory diseases, are driven by activation of inflammasomes, leading to IL-1b-mediated conditions with distinct clinical presentations (1–5)
NLRP3 is an inflammasome sensor, whose activation leads to a variety of autoinflammatory diseases (NLRP3AIDs), including three well-documented periodic fever syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular syndrome, known as neonatal-onset multisystem inflammatory disease (CINCA/NOMID) (10–15)
In many reports of germline NLRP3 mutations, the amino acid positions are mismatched to the canonical amino acid positions reported in the US National Library of Medicine NCBI and Ensembl as a result of the protein sequence being counted from the second methionine (M3) instead of M1 due to better alignment of the Kozak consensus sequence with the M3 (59, 128)
Summary
Inflammasomopathies, types of autoinflammatory diseases, are driven by activation of inflammasomes, leading to IL-1b-mediated conditions with distinct clinical presentations (1–5). Among CAPS, FCAS is the mildest phenotype, requiring a trigger such as cold temperature to cause symptom onset, while CINCA/NOMID is the most severe phenotype with onset in neonates, without a need for a trigger and often with neurological consequences (20). While both FCAS and MWS are known heritable conditions with a familial autosomal dominant pattern of inheritance (21, 22), CINCA/NOMID is sporadic and attributed to de novo mutations in NLRP3
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