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J. Biol. Chem., Vol. 283, Issue 16, 10330-10338, April 18, 2008

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Pepsinogen C Proteolytic Processing of Surfactant Protein B^*

Kristin D. Gerson, Cherie D. Foster, Peggy Zhang, Zhenguo Zhang, Michael M. Rosenblatt, and Susan H. Guttentag¹

From the Division of Neonatology, Department of Pediatrics, The University of Pennsylvania School of Medicine and the Protein Core Facility, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

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 Met³⁰² in addition to an amino-terminal cleavage at Ser¹⁹⁷. 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.

Received for publication, September 7, 2007 , and in revised form, February 1, 2008.

^* These studies were supported by National Institutes of Health Grants HL059959 (to S. G.) and HL077266 (to C. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: Abramson Research Center 416G, Children'sHospitalofPhiladelphia, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318. Fax: 215/590-4267; E-mail: guttentag{at}email.chop.edu.

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