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© The Rockefeller University Press, 0022-1007/1997/10/1087/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 1087-1098

Articles

Two Novel Routes of Transporter Associated with Antigen Processing (TAP)-independent Major Histocompatibility Complex Class I Antigen Processing

Heidi Link Snyder*, Igor Bacík*, Jack R. Bennink*, Grainne Kearns{ddagger}, Timothy W. Behrens{ddagger}, Thomas Bächi§, Marian Orlowski, and Jonathan W. Yewdell*

From the * Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892-0440; the {ddagger} Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455; the § Electron Microscopy Laboratory, University of Zurich, Zurich, Switzerland CH-8091; and the Mount Sinai School of Medicine of the City University of New York, Department of Pharmacology, New York 10029

Jaw1 is an endoplasmic reticulum (ER) resident protein representative of a class of proteins post translationally inserted into membranes via a type II membrane anchor (cytosolic NH2 domain, lumenal COOH domain) in a translocon-independent manner. We found that Jaw1 can efficiently deliver a COOH-terminal antigenic peptide to class I molecules in transporter associated with antigen processing (TAP)-deficient cells or cells in which TAP is inactivated by the ICP47 protein. Peptide delivery mediated by Jaw1 to class I molecules was equal or better than that mediated by the adenovirus E3/19K glycoprotein signal sequence, and was sufficient to enable cytofluorographic detection of newly recruited thermostabile class I molecules at the surface of TAP-deficient cells. Deletion of the transmembrane region retargeted Jaw1 from the ER to the cytosol, and severely, although incompletely, abrogated its TAP-independent peptide carrier activity. Use of different protease inhibitors revealed the involvement of a nonproteasomal protease in the TAP-independent activity of cytosolic Jaw1. These findings demonstrate two novel TAP-independent routes of antigen processing; one based on highly efficient peptide liberation from the COOH terminus of membrane proteins in the ER, the other on delivery of a cytosolic protein to the ER by an unknown route.

Address correspondence to J.R. Bennink and J.W. Yewdell, Room 213, Building 4, NIH, Bethesda, MD 20892-0440. Phone: 301-496-7533; FAX: 301-402-7362; E-mail: jy5v{at}nih.gov, jb62m{at}nih.gov

1 Abbreviations used in this paper: BFA, brefeldin A; ER, endoplasmic reticulum; FBS, fetal bovine serum; MOI, multiplicity of infection; NP, nucleoprotein; rVV, recombinant vaccinia virus; TAP, transporter associated with antigen processing; VV, vaccinia virus.


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