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Antigen Processing (Major Hbitocompatlbility Complex/Class I Moecules/Lymphokines) YOUNG YANG, JAMES B

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Antigen Processing (Major Hbitocompatlbility Complex/Class I Moecules/Lymphokines) YOUNG YANG, JAMES B Proc. Nati. Acad. Sci. USA Vol. 89, pp. 4928-4932, June 1992 Immunology Proteasomes are regulated by interferon y: Implications for antigen processing (major hbitocompatlbility complex/class I moecules/lymphokines) YOUNG YANG, JAMES B. WATERS, KLAUS FROH, AND PER A. PETERSON Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 Communicated by Frank J. Dixon, February 27, 1992 ABSTRACT Class I major histocompatibility complex strengthened by the findings, presented in this communica- (MHC) molecules present antigenic peptides of cytoplasmic tion, that several proteasomal subunits, including MHC- origin to T cells. As the lengths ofthese peptides seem stried encoded subunits, are regulated by interferon y (IFN--y) and to eight or nine amino acids, an unusual proteolytic system that the incorporation of several more subunits into protea- must play a role in antigen processing. Proteasomes, a major somes appears to depend on the expression of the MHC- extralysosomal proteolytic system, are responsible for the encoded proteasomal subunits. Moreover, the pattern of degradation of cytoplasmic proteins. We demonstrate that expression of IFN-y-regulated subunits suggests complexi- several proteasomal subunits, including MHC-encoded sub- ties in the regulation of proteasomes with respect to its units, are regulated by interferon y. These data and the finding subunit composition, subcellular localization, and its incor- that MHC-encoded and other interferon -regulated protea- poration into larger ubiquitin-related proteolytic complexes. somal subunits are uniquely associated with proteasomes Possible functions for the MHC-encoded and IFN-y- strongly suggest that the immune system has recruited protea- regulated proteasomal subunits in antigen processing are somes for antigen processing. discussed. Major histocompatibility complex (MHC) class I molecules MATERIALS AND METHODS are believed to primarily obtain antigenic peptides from Cell Cultures. HeLa cells (ATCC CCL185) were grown in proteins synthesized within the cell (1). The recent observa- Dulbecco's modified Eagle's medium (DMEM; GIBCO) sup- tion that a putative transmembrane peptide transporter (2-6) plemented with 8% fetal calf serum, 2 mM glutamine, peni- is essential for peptide loading onto class I molecules sug- cillin (100 ,ug/ml), and streptomycin (100 pug/ml). Spleno- gests that antigenic peptides, which are acquired by class I cytes offour different H-2 haplotypes (H-2k, H-2s, H-2d, and molecules in a pre-Golgi compartment (7-9), may arise in the H-2q), T1 and T2 cells (24), and murine astrocytes were cytoplasm. However, the proteolytic system responsible for grown in RPMI 1640 medium. generating class I MHC binding peptides has remained enig- Metabolic Radiag and Immunoprecipitaton. Meta- matic. bolic labeling of cells was carried out as described (25) with The majority ofproteolytic activity in the cytoplasm can be the following modifications. Unless otherwise stated, cells attributed to the activity of proteasomes (10, 11). This major were treated with IFN-y (2500 units/ml) for 96 hr prior to the extralysosomal proteolytic system (10) relies on a complex metabolic labeling. Pulse media contained 0.15 mCi of series of enzymatic events where proteins become targeted L-[35S]methionine per ml and 0.15 mCi of L-[35S]cystine per for degradation by covalent conjugation to the polypeptide ml (Amersham; 1 Ci = 37 GBq) in methionine- and cystine- ubiquitin (12, 13). The ubiquitinated protein is subsequently deficient DMEM. Cells were routinely labeled for 4 hr degraded into small peptides and free amino acids in an followed by chase periods of different lengths of time (up to ATP-dependent process by 26S ubiquitin-dedicated protea- 36 hr) in the presence of normal culture medium. Immuno- some complexes. This 26S proteasome complex contains the precipitations (25), SDS/PAGE (26), and fluorography (27) 19S form of the proteasome as its major proteolytic compo- were carried out as described (25). First-dimension nonequi- nent (14). The 19S proteasome also exists in free form in the librium pH gradient gel electrophoresis (using Ampholines cell and may represent an independent and separately regu- pH 3.5-10) was done as described (28). lated proteolytic system (14, 15). The proteasome displays Antisera and Materials. Rabbit anti-human and anti-rat several distinct peptidase activities, being able to cleave on proteasome sera were kindly provided by A. Ichihara (29). the carboxyl side of basic, acidic, and neutral amino acids, IFN-y from human T lymphocytes was obtained from Boeh- which suggests it can generate a wide variety ofpeptides from ringer Mannheim. Mouse IFN-y was obtained from Genen- diverse protein substrates (10, 11). In addition, the enzymatic tech and Amgen Biologicals. activity of the proteasome is regulated by a number of Homogenization of HeLa Cells. Two milliliters of isotonic different compounds, including nucleotides and polycations sucrose solution was added to HeLa cell monolayer. Cells (16, 17). These observations make the proteasome an attrac- were scraped from dishes and homogenized directly by 45 tive candidate as a proteolytic generator ofantigenic peptides passages through a precision clearance between the wall of a of cytoplasmic origin for class I MHC molecules (18). This metal chamber and a metal ball bearing of a Dounce homog- suggestion is further supported by the recent findings that enization vessel (30). During homogenization, the homoge- two proteasomal subunits are encoded in the MHC region nates were monitored using phase-contrast microscopy to (19-23). assess the number of broken cells, the number of intact and The view that the proteasome is a proteolytic generator of clean nuclei, and the absence of cytoplasmic clumps. antigenic peptides for class I MHC molecules is further Ammonium Sulfate Fractionation of HeLa Cell Homoge- nates. Homogenized HeLa cells, untreated and IFN-y- The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: MHC, major histocompatibility complex; IFN-y, in accordance with 18 U.S.C. §1734 solely to indicate this fact. interferon 'y; 2D, two-dimensional. 4928 Downloaded by guest on September 27, 2021 Immunology: Yang et al. Proc. Natl. Acad. Sci. USA 89 (1992) 4929 treated, were centrifuged to remove nuclei and cell debris, peared completely (spots 2, 10, 15, and 16) following IFN-y and the resultant supernatants were subjected to ammonium treatment. In addition, the intensity of spot 9 increased sulfate fractionation as described (31). 26S proteasomes considerably as a consequence of the IFN-y treatment. present in the supernatant were selectively precipitated with Experiments identical to those described above were also ammonium sulfate at 38% saturation; 19S proteasomes pre- carried out with a murine astrocyte cell line. The subunit sent in the supernatant after the 38% fractionation step were pattern of murine proteasomes was very similar to that precipitated at 60%o ammonium sulfate (32). observed for human proteasomes and the effect of IFN-y on Fractionation of Microsomes and Cytosol. Untreated and the astrocyte proteasomes was analogous to that ofthe HeLa IFN--treated HeLa cells were labeled for 4 hr, homoge- cell proteasomes (not shown). Thus, the subunit composition nized, and subjected to differential centrifugation. The ho- of proteasomes from two species is regulated by IFN-y. mogenates were first spun at 13,000 rpm for 30 min to remove If the IFN-y-regulated proteasomal subunits are involved nuclei and cell debris. The resulting supernatants were then in the generation ofantigenic peptides, one might assume that spun at 100,000 x g for 30 min to pellet microsomes. cells that express high levels of class I MHC molecules may Proteasomes in the supernatant fractions (cytosolic fraction) also constitutively express high levels ofthe IFN-y-regulated and in the pellets (crude microsomal fraction) were separately proteasomal subunits. For this reason we chose to examine immunoprecipitated and analyzed by two-dimensional (2D) proteasomes from murine splenocytes. In addition, we could gel electrophoresis. also determine if proteasomal subunits displayed structural polymorphisms indicative of many MHC-encoded proteins. Proteasomes from biosynthetically labeled splenocytes de- RESULTS rived from four mouse strains representing the H-2 haplo- Proteasomal Subunit Composition Is Regulated by IFN-y. types d, k, s, and q were immunoprecipitated with an The assembly of class I MHC molecules in the endoplasmic antiserum specific for rat proteasomes and subjected to 2D reticulum in transfected cells that overexpress class I heavy PAGE. The typical patterns of the proteasomal subunits are chains and f32-microglobulin is limited by the availability of depicted in Fig. 2. All but one ofthe proteasomal polypeptide peptides that can bind to class I MHC molecules. This spots occurred at corresponding positions for all four haplo- restriction can be overcome by treating the cells with IFN-y types. The exception was spot 9, which is likely to corre- (E. Song, Y.Y., M. R. Jackson, and P.A.P., unpublished spond to one of the MHC-encoded subunits (19-23) and work). IFN-y induces changes in the level of expression of a which obviously occurs in at least two allelic forms (21). The number ofgene products affecting various cellular responses splenocyte proteasomal subunit pattern was intermediate that appear
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