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MHC Class I Antigen Presentation Precursors, but Is Not Required for Most Peptidase Needed to Trim Long Antigenic Tripeptidyl Pe

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MHC Class I Antigen Presentation Precursors, but Is Not Required for Most Peptidase Needed to Trim Long Antigenic Tripeptidyl Pe Tripeptidyl Peptidase II Is the Major Peptidase Needed to Trim Long Antigenic Precursors, but Is Not Required for Most MHC Class I Antigen Presentation This information is current as of May 2, 2019. Ian A. York, Nidhi Bhutani, Sophia Zendzian, Alfred L. Goldberg and Kenneth L. Rock J Immunol 2006; 177:1434-1443; ; doi: 10.4049/jimmunol.177.3.1434 http://www.jimmunol.org/content/177/3/1434 Downloaded from References This article cites 45 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/177/3/1434.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on May 2, 2019 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Tripeptidyl Peptidase II Is the Major Peptidase Needed to Trim Long Antigenic Precursors, but Is Not Required for Most MHC Class I Antigen Presentation1 Ian A. York,2* Nidhi Bhutani,3† Sophia Zendzian,* Alfred L. Goldberg,† and Kenneth L. Rock* Recent reports concluded that tripeptidyl peptidase (TPPII) is essential for MHC class I Ag presentation and that the proteasome in vivo mainly releases peptides 16 residues or longer that require processing by TPPII. However, we find that eliminating TPPII from human cells using small interfering RNA did not decrease the overall supply of peptides to MHC class I molecules and reduced only modestly the presentation of SIINFEKL from OVA, while treatment with proteasome inhibitors reduced these processes dramatically. Purified TPPII digests peptides from 6 to 30 residues long at similar rates, but eliminating TPPII in cells reduced the processing of long antigenic precursors (14–17 residues) more than short ones (9–12 residues). Therefore, TPPII appears to be the major peptidase capable of processing proteasome products longer than 14 residues. However, proteasomes in Downloaded from vivo (like purified proteasomes) release relatively few such peptides, and these peptides processed by TPPII require further trimming in the endoplasmic reticulum (ER) by ER aminopeptidase 1 for presentation. Taken together, these observations demonstrate that TPPII plays a specialized role in Ag processing and one that is not essential for the generation of most presented peptides. Moreover, these findings reveal that three sequential proteolytic steps (by proteasomes, TPPII, and then ER aminopep- sidase 1) are required for the generation of a subset of epitopes. The Journal of Immunology, 2006, 177: 1434–1443. ntigen-specific cytotoxic CD8ϩ T lymphocytes recog- peptidase 1 (ERAP1) (9, 10) (also known as ER aminopeptidase http://www.jimmunol.org/ nize short peptides that are bound to MHC class I mol- associated with Ag processing or ERAAP (11)), an IFN-␥-induced A ecules (MHC class I) on the cell surface. The great ma- aminopeptidase in the ER. Trimming of N-extended precursors can jority of the peptides associated with MHC class I are derived from also occur in the cytosol. Although there are many cytosolic amin- cell proteins, most of which are degraded by the proteasome (re- opeptidases, whether they perform specific functions in Ag pre- viewed in Refs. 1–3). Purified 26S and 20S proteasomes degrade sentation, and their relative importance, is presently unclear. proteins to peptides of 3–22 aa long whose length follows a log Recently, several studies have also suggested an important role normal distribution (4, 5). Although 70–80% of proteasome prod- in Ag processing for tripeptidyl peptidase II (TPPII). This enzyme ϳ ucts are too small to serve as MHC class I epitopes, 10% of is an exceptionally large (2–9 megadaltons) cytosolic peptidase by guest on May 2, 2019 peptides are 8–10 residues long, the size required for strong bind- that removes groups of three residues from the N terminus of pep- ing to MHC class I complexes. Another 10–15% of peptides are tide substrates (tripeptidyl exopeptidase activity) and has also been too long to bind directly to MHC class I molecules but may serve reported to have a weak endoprotease activity (12). Recent studies as precursors for MHC class I-binding peptides (4–6). Several have suggested that TPPII may play two roles in MHC class I Ag lines of evidence have shown that proteasome cleavages generate presentation. One reported function is to make the endoproteolytic the C-terminal residue of MHC class I-binding peptides (7, 8). cleavages necessary to generate a presented peptide, as has been However, mature epitopes can be efficiently generated in vivo reported in the processing for HIV Nef73–82 (13). However, it is from N-extended precursors (7, 8). This trimming process requires unlikely that TPPII frequently generates the C-terminal residues, a a free N terminus (8) and is therefore mediated by aminopepti- function normally served by proteasomes. Early studies had sug- dases. One such aminopeptidase which plays an important role in gested that TPPII may even substitute for the proteasome in the Ag presentation in vivo is endoplasmic reticulum (ER)4 amino- degradation of cell proteins and generation of most antigenic pep- tides (14); however, these suggestions have not been substantiated. A second role proposed for TPPII is in trimming the N-terminal *Department of Pathology, University of Massachusetts Medical School, Worcester, extensions from long precursor peptides (15). It has been sug- MA 01655; and †Department of Cell Biology, Harvard Medical School, Boston MA gested, based on studies in cultured cells with inhibitors, that 02115 among cytosolic peptides, only TPPII can trim peptides longer Received for publication February 8, 2006. Accepted for publication April 28, 2006. than ϳ16 aa (16), consistent with previous biochemical studies The costs of publication of this article were defrayed in part by the payment of page establishing that other cytosolic peptidases (e.g., thimet oligopep- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tidase (TOP) (16) and various aminopeptidases (15)) have little activity against peptides longer than ϳ13–15 residues. Remark- 1 This work was supported by grants from the National Institutes of Health (to K.L.R.). ably, in these experiments inhibiting TPPII reduced Ag presenta- 2 Address correspondence and reprint requests to Dr. Ian A. York, Department of tion to the same extent as did inhibitors of the proteasome. More- Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, over, inhibiting both TPPII and proteasomes had no greater effect, Worcester, MA 01655. E-mail address: [email protected] which led to the surprising conclusion that TPPII was essential for 3 Current address: Department of Molecular Pharmacology, Stanford University School of Medicine, Palo Alto, CA 94305. 4 ␤ ␤ Abbreviations used in this paper: ER, endoplasmic reticulum; TPPII, tripeptidyl somal entry site; TOP, thimet oligopeptidase; 2-m, 2-microglobulin; AAF-amc, peptidase II; HC, heavy chain; siRNA, small interfering RNA; IRES, internal ribo- Ala-Ala-aminomethyl coumarin; VSV, vesicular stomatitis virus. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 1435 MHC class I Ag presentation (16, 17). Moreover, because inhib- Small interfering RNA (siRNA) iting TPPII only affected the trimming of peptides longer than 15 siRNA was obtained from Qiagen. TPPII-specific siRNA was 5Ј-AAG residues in length, Reits et al. (16) concluded that proteasomes CAACTCACTGGCCAAATT-3Ј and 5Ј-AATTTGGCCAGTGAGTTGC- must be generating predominately precursor peptides that are 16 3Ј. As a control, we used siRNA directed against murine TOP, which does residues or longer, in clear contrast to findings on the size distri- not have a target sequence in human cells, as previously described (10). bution of peptides produced by purified proteasomes (4–6). It was siRNA directed against ERAP1 has been previously described (10). RNA oligos were annealed and prepared, and cells were transfected with siRNA therefore postulated that intracellular proteasomes behave differ- using Oligofectamine (Invitrogen Life Technologies), as previously de- ently in vivo than they do after purification. These findings led to scribed (10). Based on preliminary experiments, cells were analyzed 3 or a model in which proteasomes make the initial cleavages in Ags to 4 days after transfection. To confirm the efficacy of knockdown by PCR, generate oligopeptides of 16 or more residues, and then TPPII mRNA was collected from cells (RNeasy kit; Qiagen) and PCR was per- formed using TPPII-specific primers 5Ј-GGTGGGCAAGTCTCAGT plays an essential role in shortening the N-terminal extensions on GAT-3Ј and 5Ј-CATCAAAGCGGTTGATTCCT-3Ј, or control primers these peptides to a size where other aminopeptidases could trim the specific for ERAP1: 5Ј-GGGAGCTGGAGAGAGGCTAT-3Ј and products of TPPII down to mature epitopes or to individual amino 5Ј-CTTGCTTTGAAGGCAGGTTC-3Ј. acids (16, 17). Plasmids In this study, we examine the role of TPPII in trimming peptides for MHC class I Ag presentation. Initial studies on the purified Plasmid pUG1 was constructed using ubiquitin cDNA (provided by L. Whitton, The Scripps Research Institute, La Jolla, CA), modified to have enzyme showed that TPPII is in fact not selective for long pep- SfoI and BamHI sites at the 3Ј end.
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