Structural Insights into SPLUNC1's Role in Cystic Fibrosis Lung Disease

The ability to maintain proper airway surface liquid (ASL) volume homeostasis is vital for mucus hydration and clearance, which are essential aspects of the mammalian lung’s innate defense system. In cystic fibrosis (CF), one of the most common life-threatening genetic disorders, ASL dehydration leads to mucus accumulation and chronic infection.  In normal airways, the secreted protein Short Palate Lung and Nasal epithelial Clone 1 (SPLUNC1) effectively inhibits Epithelial Na⁺ Channel (ENaC)-dependent Na⁺ absorption and preserves ASL hydration and mucus clearance. In CF airways, increased ENaC-dependent Na⁺ absorption contributes to ASL depletion and hence increased disease.  However, the mechanism for abnormal ENaC regulation in CF airways has remained elusive. Here we show that SPLUNC1 is a pH-sensitive regulator of ENaC that is unable to inhibit ENaC in the acidic CF microenvironment.   To better understand the interaction between ENaC and SPLUNC1, we resolved the crystal structure of SPLUNC1 to 2.8 Å. Notably, this structure revealed two pH-sensitive salt bridges which when removed, rendered SPLUNC1 pH-insensitive and able to regulate ASL volume in acidic CF ASL.  Thus, we conclude that ENaC hyperactivity is secondary to reduced CF ASL pH. Together, these data provide molecular insights into the mucosal dehydration associated with a range of pulmonary diseases, including CF, and suggest that future therapy be directed towards alkalinizing the pH of CF airways.

Bio

Robert Tarran did his B.Sc. at the University of Leeds, UK and his Ph.D. at the University of Newcastle upon Tyne, UK. For his PhD, he performed electrophysiological studies on CFTR in native airway epithelia.  After postdoctoral positions at The University of North Carolina (UNC) at Chapel Hill and at the University of California at Berkeley, he obtained a faculty position at UNC-Chapel Hill. He is currently an Associate Professor in the Department of Cell Biology and Physiology at UNC-Chapel Hill and the Director of the UNC Tobacco Center for Regulatory Science.  His research interests including studying the pathophysiology of cystic fibrosis and chronic obstructive lung disease (COPD).  He has a long standing interest in the regulation of ion channels in the airways and in helping to develop novel therapies to treat chronic lung disease. 

Further info: https://www.med.unc.edu/cellbiophysio/faculty/tarran