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J. Biol. Chem., Vol. 279, Issue 16, 16178-16184, April 16, 2004

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Processing of Pulmonary Surfactant Protein B by Napsin and Cathepsin H^*

Takayuki Ueno, Stig Linder, Cheng-Lun Na, Ward R. Rice, Jan Johansson¶, and Timothy E. Weaver||

From the Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute and Hospital, SE-171 76 Stockholm, Sweden, the ^¶Department of Molecular Biosciences, Swedish University of Agricultural Sciences, the Biomedical Center, SE-751 23, Uppsala, Sweden, and the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039

Surfactant protein B (SP-B) is an essential constituent of pulmonary surfactant. SP-B is synthesized in alveolar type II cells as a preproprotein and processed to the mature peptide by the cleavage of NH₂- and COOH-terminal peptides. An aspartyl protease has been suggested to cleave the NH₂-terminal propeptide resulting in a 25-kDa intermediate. Napsin, an aspartyl protease expressed in alveolar type II cells, was detected in fetal lung homogenates as early as day 16 of gestation, 1 day before the onset of SP-B expression and processing. Napsin was localized to multivesicular bodies, the site of SP-B proprotein processing in type II cells. Incubation of SP-B proprotein from type II cells with a crude membrane extract from napsin-transfected cells resulted in enhanced levels of a 25-kDa intermediate. Purified napsin cleaved a recombinant SP-B/EGFP fusion protein within the NH₂-terminal propeptide between Leu¹⁷⁸ and Pro¹⁷⁹, 22 amino acids upstream of the NH₂ terminus of mature SP-B. Cathepsin H, a cysteine protease also implicated in pro-SP-B processing, cleaved SP-B/EGFP fusion protein 13 amino acids upstream of the NH₂ terminus of mature SP-B. Napsin did not cleave the COOH-terminal peptide, whereas cathepsin H cleaved the boundary between mature SP-B and the COOH-terminal peptide and at several other sites within the COOH-terminal peptide. Knockdown of napsin by small interfering RNA resulted in decreased levels of mature SP-B and mature SP-C in type II cells. These results suggest that napsin, cathepsin H, and at least one other enzyme are involved in maturation of the biologically active SP-B peptide.

Received for publication, November 3, 2003 , and in revised form, February 5, 2004.

^* This work was supported by Grant R37-HL56285 from the National Institutes of Health (to T. E. W.) and by a grant from Cancerföreningen in Stockholm (to S. L.) 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.

^|| To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-7223; Fax: 513-636-7868; E-mail: Tim.Weaver{at}cchmc.org.

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