Tapt1 deficiency in mice impairs pulmonary lipid homeostasis and normal postnatal respiration by targeting ABCA3 for autophagy-lysosomal degradation.

内容摘要

TAPT1, which encodes a highly conserved multi-pass transmembrane protein termed transmembrane anterior posterior transformation 1 (TAPT1), has been reported as a disease-causing gene, but its physiological role in mice remains to be elucidated. Using Tapt1 knockout and knock-in mice, we indicate that TAPT1 localizes to the endoplasmic reticulum and that Tapt1 deletion causes neonatal lethality due to atelectasis-induced respiratory distress. We further reveal that TAPT1 interacts with the ATP-binding cassette transporter A3 (ABCA3), thereby regulating autophagy-lysosomal degradation of ABCA3. ABCA3 insufficiency reduces surfactant lipids, leading to defective lamellar body formation and surfactant production. This study presents a hitherto unrecognized pathway for ABCA3 protein degradation. Our findings may advance the understanding of genetic determinants of neonatal respiratory distress syndrome, providing valuable insights into the treatment of lung surfactant disorders.