Am. J. Respir. Cell Mol. Biol., Volume 26, Number 6, June, 2002 659-670

Involvement of Cathepsin H in the Processing of the Hydrophobic Surfactant-Associated Protein C in Type II Pneumocytes

Frank Brasch, Anja ten Brinke, Georg Johnen, Matthias Ochs, Nadine Kapp, Klaus M. Müller, Michael F. Beers, Heinz Fehrenbach, Joachim Richter, Joseph J. Batenburg, and Frank Bühling

Division of Electron Microscopy, Department of Anatomy, University of Göttingen, Göttingen, Germany; Institute of Pathology, University Hospital "Bergmannsheil," Bochum, Germany; Department of Biochemistry and Cell Biology, Utrecht University, Utrecht, The Netherlands; Biochemical Pharmacology, Faculty of Science, Department of Biology, University of Konstanz, Konstanz, Germany; Lung Epithelial Cell Biology Laboratories, Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Institute of Pathology, Carl Gustav Carus University, Dresden, Germany; and Institute of Immunology, University of Magdeburg, Magdeburg, Germany

Surfactant protein C (SP-C) is synthesized by type II pneumocytes as a 21-kD propeptide (proSP-C) which is proteolytically processed to a 4.2-kD dipalmitoylated protein. To characterize the processing of proSP-C and the role of the cysteine protease cathepsin H, we studied the localization of proSP-C and cathepsin H in human as well as proSP-C in rat lungs, the enzymatic cathepsin H activity in isolated rat lamellar bodies, and the cleavage of human proSP-C by purified cathepsin H. Using antisera directed against the N-terminal E¹¹-R²³ (NPROSP-C^11-23), the C-terminal G¹⁶²-G¹⁷⁴ domain (CPROSP-C^162-174) of proSP-C, and against cathepsin H, immunogold labeling identified all three in electron-dense multivesicular bodies, but only NPROSP-C^11-23 and cathepsin H in composite as well as lamellar bodies of type II pneumocytes. Immuno double-labeling further distinguished electron-dense vesicles containing cathepsin H or electron light vesicles/multivesicular bodies containing proSP-C. Isolated lamellar bodies contained enzymatically active cathepsin H, a 6-kD proSP-C processing intermediate detected only by NPROSP-C^11-23, and mature SP-C. Using enzyme activities comparable to those in isolated lamellar bodies, purified cathepsin H generated a partially N-terminal processed proSP-C intermediate in vitro. In conclusion, our results indicate that after the fusion of electron-dense vesicles containing cathepsin H and electron-light vesicles or multivesicular bodies containing proSP-C, cathepsin H is involved in the first N-terminal processing step of proSP-C in electron-dense multivesicular bodies of type II pneumocytes.

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