Is the SPLUNC1-Orai1 axis a critical determinant of lung health?

Abstract

Short palate lung and nasal epithelial clone 1 (SPLUNC1; gene name BPIFA1) is a secreted protein that is highly expressed in the nasopharyngeal and pulmonary systems. By data mining, we found that SPLUNC1 is also expressed in other organs, including the kidneys and the pituitary gland. SPLUNC1 is an asthma and cystic fibrosis gene modifier that also inversely correlates with the severity of bronchiectasis. Orai1 is a plasma membrane Ca2+ channel that is an essential regulator of the immune system. We previously found that SPLUNC1 binds to Orai1, causing it to be ubiquitinated, internalized and trafficked to the lysosome for degradation, thus reducing Ca2+ signaling. Here, we discuss how dysregulation of SPLUNC1-Orai1 interactions may contribute to hyperinflammation in multiple pulmonary diseases. We, and others, have also targeted Orai1 therapeutically, and we will also discuss how Orai1 inhibition may overcome SPLUNC1 deficiency and be beneficial for the treatment of chronic lung disease.