The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/1105/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1105-1116

Articles

Major Histocompatibility Complex Class I Viral Antigen Processing in the Secretory Pathway Defined by the trans-Golgi Network Protease Furin

Beatriz C. Gil-Torregrosa, A. Raúl Castaño, and Margarita Del Val

From the Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, 28220 Madrid, Spain

Classical antigen presentation by major histocompatibility complex class I molecules involves cytosolic processing of endogenously synthesized antigens by proteasomes and translocation of processed peptides into the endoplasmic reticulum (ER) by transporters associated with antigen presentation (TAP). Alternative pathways for processing of endogenous antigens, generally involving the ER, have been suggested but not fully proved. We analyzed the potential for class I presentation of proteolytic maturation of secretory antigens in the exocytic pathway. We found that hepatitis B (HB) virus secretory core protein HBe can efficiently deliver COOH-terminally located antigenic peptides for endogenous class I loading in the absence of TAP. Antigen presentation to specific cytotoxic T lymphocytes correlates with protein maturation at the COOH terminus, since modification of maturation and transport of HBe through the secretory pathway alters antigen presentation. Both maturation and a necessary processing step occur in the Golgi or post-Golgi compartment. Antigen presentation is independent of proteasome activity, but inhibitors of the trans-Golgi network resident protease furin inhibit both HBe maturation and antigen presentation. These results define a new antigen processing pathway located in the secretory route, with a central role for proteolytic maturation mediated by the subtilisin protease family member furin as an efficient source for antigen presentation.

Key Words: antigen processing • major histocompatibility complex class I • secretory pathway • furin • virus

Address correspondence to Margarita Del Val, Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, Ctra Pozuelo, Km 2, E-28220 Majadahonda (Madrid), Spain. Phone: 34-91-5097943; Fax: 34-91-5097918; E-mail: mdval{at}isciii.es

The inhibitors lactacystin and decRVKR-CMK were kindly provided by Drs. S. Omura and W. Garten, respectively. The cell lines were gifts from Drs. H.-G. Rammensee, G. Hämmerling, P. Cresswell, and U.H. Koszinowski. We thank Drs. U.H. Koszinowski and H.-J. Schlicht for rVV, and Hoffmann-La Roche for recombinant human IL-2. The excellent technical assistance of F. Vélez is gratefully acknowledged.

Abbreviations used: BFA, brefeldin A; ER, endoplasmic reticulum; HBV, hepatitis B virus; rVV, recombinant vaccinia virus; TAP, transporter associated with antigen processing; TGN, trans-Golgi network.


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