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J Biol Chem, Vol. 273, Issue 24, 15287-15293, June 12, 1998

Synthetic Processing of Surfactant Protein C by Alevolar Epithelial Cells
THE COOH TERMINUS OF proSP-C IS REQUIRED FOR POST-TRANSLATIONAL TARGETING AND PROTEOLYSIS

Michael F. Beers^§, Catherine A. Lomax, and Scott J. Russo

From the  Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6068 and the ^§ Pulmonary and Critical Care Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104

Surfactant protein C (SP-C) is synthesized by alveolar type II cells as a 21-kDa propeptide (proSP-C₂₁) which is proteolytically processed in subcellular compartments distal to the trans-Golgi network to yield a 35-residue mature form. Initial synthetic processing events for SP-C include post-translational cleavages of the COOH terminus of proSP-C₂₁ yielding two intermediates (16 and 6 kDa). To test the role of specific COOH-terminal domains in intracellular targeting and proteolysis of proSP-C₂₁, synthesis and processing of SP-C was evaluated using a lung epithelial cell line (A549) transfected with a eukaryotic expression vector containing either the full-length cDNA for rat SP-C (SP-C^wt) or one of six polymerase chain reaction (PCR)-generated COOH terminally truncated forms (SP-C^1-185, SP-C^1-175, SP-C^1-147, SP-C^1-120, SP-C^1-72, and SP-C^1-59). Using in vitro transcription/translation, each of the seven constructs produced a ³⁵S-labeled product of appropriate length which could be immunoprecipitated by epitope specific proSP-C antisera. Immunoprecipitation of ³⁵S-labeled A549 cell lysates from SP-C^wt transfectants demonstrated rapid synthesis of [³⁵S]proSP-C₂₁ with processing to SP-C₁₆ and SP-C₆ intermediates via cleavages of the COOH-terminal propeptide. Both the intermediates as well as the kinetics of processing in A549 cells were similar to that observed in rat type II cells. In contrast, constructs SP-C^1-185, SP-C^1-175, SP-C^1-147, SP-C^1-120, SP-C^1-72, and SP-C^1-59 were each translated but degraded without evidence of proteolytic processing. Fluorescence immunocytochemistry identified proSP-C^wt in cytoplasmic vesicles of A549 cells while all COOH-terminal deletional mutants were restricted to an endoplasmic reticulum/Golgi compartment identified by co-localization with fluorescein isothiocyanate-concanavalin A. We conclude that SP-C^wt expressed in A549 cells is directed to cytoplasmic vesicles where it is proteolytically processed in a manner similar to native type II cells and that amino acids Cys¹⁸⁶-Ile¹⁹⁴ located at the COOH terminus of proSP-C₂₁ are necessary for correct intracellular targeting and subsequent cleavage events.

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