Pepsinogen C proteolytic processing of surfactant protein B.
Surfactant protein B (SP-B) is essential to the function of pulmonary surfactant and to lamellar body genesis in alveolar epithelial type 2 cells. The bioactive, mature SP-B is derived from multistep post-translational proteolysis of a larger proprotein. The identity of the proteases involved in carboxyl-terminal cleavage of proSP-B remains uncertain. This cleavage event distinguishes SP-B production in type 2 cells from less complete processing in bronchiolar Clara cells. We previously identified pepsinogen C as an alveolar type 2 cell-specific protease that was developmentally regulated in the human fetal lung. We report that pepsinogen C cleaved recombinant proSP-B at Met(302) in addition to an amino-terminal cleavage at Ser(197). Using a well described model of type 2 cell differentiation, small interfering RNA knockdown of pepsinogen C inhibited production of mature SP-B, whereas overexpression of pepsinogen C increased SP-B production. Inhibition of SP-B production recapitulated the SP-B-deficient phenotype evident by aberrant lamellar body genesis. Together, these data support a primary role for pepsinogen C in SP-B proteolytic processing in alveolar type 2 cells.
Gerson
Kristin D
KD
Division of Neonatology, Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Foster
Cherie D
CD
Zhang
Peggy
P
Zhang
Zhenguo
Z
Rosenblatt
Michael M
MM
Guttentag
Susan H
SH
D000595:Amino Acid Sequence; D001980:Bronchi / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000196:embryology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D020115:Pepsinogen C / Q000737:chemistry*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D037701:Pulmonary Surfactant-Associated Protein B / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014357:Trypsin / Q000737:chemistry
D037701:Pulmonary Surfactant-Associated Protein B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D020115:Pepsinogen C; D014357:Trypsin