Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

Abstract

Significance The exact function of gasdermin-B, a protein involved in epithelial cell development, is unknown. We provide insights into gasdermin-B function and how it may contribute to cancer progression and genetic susceptibility to asthma and inflammatory bowel disease (IBD). In contrast to other gasdermins, which bind phosphoinositides and cardiolipin only upon cleavage between their N- and C-terminal domains, intact gasdermin-B binds phosphoinositides and, uniquely, sulfatide, a component of the apical membrane of epithelial cells. Polymorphism residues in the C-terminal domain, associated with asthma and IBD, induce structural changes that may affect protein activity. Components of the apical plasma membrane maintain the cell barrier integrity; thus, aberrant sulfatide levels due to changes in the cellular gasdermin-B concentration or activity could affect disease risk.