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Loading Proteasome Activity and MHC Class I Peptide Allelic Differences in the Relationship Between Allelic Differences in the Relationship Between Proteasome Activity and MHC Class I Peptide Loading This information is current as Adam M. Benham, Monique Grommé and Jacques Neefjes of September 24, 2021. J Immunol 1998; 161:83-89; ; http://www.jimmunol.org/content/161/1/83 Downloaded from References This article cites 48 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/161/1/83.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 24, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Allelic Differences in the Relationship Between Proteasome Activity and MHC Class I Peptide Loading1 Adam M. Benham, Monique Gromme´, and Jacques Neefjes2 MHC class I molecules are cell surface glycoproteins that play a pivotal role in the response to intracellular pathogens. The loading of MHC class I molecules with antigenic substrates takes place in the endoplasmic reticulum. This requires a functional TAP transporter, which translocates peptides into the endoplasmic reticulum from the cytosol. The generation of antigenic peptides from polypeptide precursors is thought to be mediated in the cytosol by the proteasome. Previously, we have demonstrated that inhibiting the proteasome with the specific covalent inhibitor lactacystin results in a direct reduction of peptide-loaded MHC class I molecules. This indicates that the proteasome is the limiting step in the MHC class I pathway. In this study we use isoelectric focusing to demonstrate that two related MHC class I alleles, HLA-A3 and HLA-A11, as well as HLA-B35 do not follow this behavior. In contrast to other class I alleles expressed by the same cells, these alleles are loaded with peptides and mature normally Downloaded from when proteasome activity is severely inhibited. Our observations highlight a new level of diversity in the MHC class I system and indicate that there are allele-specific differences in the linkage between proteasome activity and MHC class I peptide loading. The Journal of Immunology, 1998, 161: 83–89. efense against intracellular pathogens and tumor cells is studies performed with fluorogenic peptide substrates. These in- 1 mediated by CD8 T cells. These effector cells specif- clude a chymotrypsin-like activity and a trypsin-like activity, http://www.jimmunol.org/ D ically recognize foreign peptides in the context of self which catalyze scission of the peptide bond on the C-terminal side MHC class I molecules expressed at the plasma membrane, thus of hydrophobic and basic amino acids, respectively. An indepen- orchestrating the specific lysis of the infected or dysfunctional cell dent acid-like enzyme activity has been postulated to be involved (1). Antigenic peptides have to be generated from polypeptide pre- in cleavage at the N-terminus of the substrate, with the products of cursors by cytosolic protease activity (2, 3) before their transport proteasome digestion being around nine amino acids in length from the cytosol into the endoplasmic reticulum (ER)3 by the (11). In the assembled eukaryotic proteasome, only three of the ATP-dependent peptide transporter TAP (4). TAP preferentially seven types of b subunits are catalytically active. The generation translocates peptides of between 8 and 14 amino acids in length of these active sites takes place during proteasome assembly by by guest on September 24, 2021 with some sequence specificity (5, 6). Within the ER, antigenic cleavage of an N-terminal pro-sequence that exposes the catalytic peptides associate with an MHC class I heterodimer (a heavy chain threonine (12, 13). In mammals, these three catalytic subunits, b1 b and the light chain 2m) to form a functional trimeric complex. (Y/d), b2 (Z), and b5 (X/MB1), are co-ordinately replaced upon This exits the ER and traverses the Golgi apparatus where it ac- IFN-g stimulation by the active b subunits, LMP2, MECL1, and quires sialic acid modifications before arrival at the plasma LMP7, respectively (14, 15). Examination of the Saccharomyces membrane. cerevisae proteasome crystal structure suggests that the incorpo- A wealth of experimental data has implicated the proteasome in ration of LMP2 into the particle should enhance the generation of the generation of antigenic peptides (7). The proteasome is a mul- peptides with C-terminal hydrophobic and basic residues at posi- ticatalytic particle consisting of structural a subunits and catalytic tion 9 (11, 16, 17). This makes them more suitable for binding to b a b b a subunits arranged as an 7 7 7 7 cylinder (8). The proteasome MHC class I molecules that accommodate such residues in their F moves within the cell by diffusion (9) and is a member of the pockets. Consistent with this, LMP2- and LMP7-deficient mice Ntn-hydrolase family of enzymes, since active b subunits posses a and cell lines have been claimed to express diminished amounts of catalytic N-terminal threonine residue (10). Up to five types of MHC class I molecules at the cell surface, although the phenotypes catalytic activities have been ascribed to the proteasome based on are rather mild (18, 19). Functional evidence for a role of the proteasome in the class I Ag presentation pathway also comes from studies using broad Division Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, The Neth- specificity inhibitors, which block the presentation of endogenous erlands antigens to CTL (20, 21). More recently, a Streptomyces metabo- Received for publication December 2, 1997. Accepted for publication February 27, lite called lactacystin and its b-lactone derivative have been shown 1998. to bind specifically and covalently to the catalytic subunits of The costs of publication of this article were defrayed in part by the payment of page mammalian proteasomes (22–24). Irreversible inhibition of pro- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. teasomes using lactacystin specifically abolishes the presentation 1 This work was supported by European Community Fellowship EBCHBGCT930356 of a range of viral proteins to CTL (25), although this may not be (to A.B.) and Netherlands Organization for Scientific Research Grant 901-09-027 (to the case for all antigenic peptides (26). M.G.). In vivo, the proteasome interacts with modulatory protein com- 2 Address correspondence and reprint requests to Dr. Jacques Neefjes, Division Cel- plexes. Included among these is the 19S cap, which is involved in lular Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Am- sterdam, The Netherlands. E-mail address: [email protected] the targeting of ubiquitinated proteins to the proteasome (27), and g 3 Abbreviations used in this paper: ER, endoplasmic reticulum; PSI, Cbz-Ile-Glu(O- the IFN- -inducible activator PA28 (28). PA28 exists as a hex- t-Bu)-Ala-Leu; 1D-IEF, one-dimensional isoelectric focusing. amer of a and b subunits that binds at the ends of the proteasome Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 84 CLASS I ALLELES AND PROTEASOME ACTIVITY cylinder (29). Overexpression of PA28a has been shown to en- portions and assayed against 100 mM of the peptide substrates Suc-Leu- hance the generation of some Ag for presentation to CTL (30) and Leu-Val-Tyr-AMC and z-Ala-Ala-Arg-AMC (Novabiochem, La¨utelfin- in vitro, PA28 alters the pattern of peptide products generated by gen, Switzerland, and Bachem, Bubendorf, Switzerland) in a total volume of 200 ml of hypotonic buffer at 37°C. These substrates give an accurate purified 20S proteasome digests (31). However, how PA28 func- determination of the chymotrypsin-like and the trypsin-like activities of the tions in vivo with respect to the 26S proteasome complex in Ag proteasome, respectively. Aliquots of 10 ml were quenched in duplicate presentation is unresolved. into 1 ml of ethanol after 8 h, and the fluorescence of the free AMC l 5 l 5 Previously, we used the proteasome-specific inhibitor lactacys- ( excitation 370 nm, emission 460 nm) was measured using a spec- tin to demonstrate that the trypsin-like activity of the proteasome trofluorometer (Perkin-Elmer, Den Bosch, The Netherlands). Incubation buffer plus peptides, beads, or Ab alone gave negligible fluorescence. Chy- was closely correlated with the peptide loading of MHC class I motrypsin and trypsin digestion of peptides was used as a positive control. molecules in four different cell types (32). Both the trypsin-like Proteasome activity was calculated by subtracting the mean W6/32 (con- and the chymotrypsin-like activities of the proteasome became re- trol) values from the mean MCP21 values at each concentration and setting m lated to MHC class I stability after IFN-g stimulation. These re- the figure obtained at 0 M lactacystin to 100% for each substrate. Control values were always ,10% of specific values. sults indicated that in cells optimized for Ag presentation, the pro- teasome is the limiting factor in the MHC class I Ag presentation pathway. In this report we show that while this assertion holds for Biosynthetic labeling and MHC class I immunoprecipitations the majority of MHC class I alleles, it is not universal.
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