Farzana Bhuyan, Clinton Bradfield, Amitava Roy, Adriana A de Jesus, Mohammad Arif Rahman, Benjamin Schwarz, Anjelika Gasilina, Andre Rastegar, Gaurav Sachin, Christopher L Friend, Kanika Chopra, Kat Uss, Ryan Kissinger, Sara Alehashemi, Sundar Ganesan, Nathan T Brandes, Ian S Lacroix, Vinod Nair, Jacqueline M Leung, Clayton Winkler, Juraj Kabat, Steven M Holland, Philip J Kahn, Douglas B Kuhns, John Hammer, Ronit Herzog, Deborah Consolini, Iain Fraser, Raphaela Goldbach-Mansky
De novo mutations underlying early-onset systemic autoinflammatory diseases have identified key regulators of innate immunity, including pathways that drive IL-1-mmediated inflammation. Here we describe two unrelated girls presenting in infancy with systemic inflammation and sterile lung abscesses, who harbor the same de novo gain-of-function mutation in dysferlin ( DYSF ; p.P1449L) Myeloid expression of DYSF P1449L enhances COP-I binding, promotes dysferlin retention in the ER-Golgi, and disrupts vesicle trafficking and membrane homeostasis. Dysferlin-mutant monocytes and M2-like macrophages exhibit ectopic perinuclear NLRP3 inflammasome activation, increased IL-1β production, and inflammatory cell death. Mutant M2-like macrophages further display defects in membrane expansion, exocytosis, efferocytosis, and debris clearance, promoting neutrophil recruitment and DAMP-signal amplification that culminate in sterile abscess formation. These findings identify dysferlin as a regulator of membrane homeostasis in myeloid cells, establish defective membrane-stress adaptation as trigger of NLRP3 inflammasome activation, and define a novel IL-1 mediated autoinflammatory disease caused by gain-of-function DYSF mutations.