The Unique Functions of Tissue-Specific Proteasomes
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Erschienen in: Trends in Biochemical Sciences ; 39 (2014), 1. - S. 17-24 https://dx.doi.org/10.1016/j.tibs.2013.10.004 The unique functions of tissue-specific proteasomes 1 1,2 Andrea Kniepert and Marcus Groettrup 1 Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany 2 Biotechnology Institute Thurgau at the University of Konstanz, CH-8280 Kreuzlingen, Switzerland The 26S proteasome is the main protease in eukaryotes. specialization of substrate specificity of these three b sub- Proteolysis occurs within the cylindrical 20S proteasome units, which is measured via the hydrolysis of small fluoro- that is constitutively expressed in most tissues. Howev- genic peptides with certain amino acids in the P1 position. er, three tissue-specific versions of the 20S proteasome These define the chymotrypsin-like activity (cleavage after have been discovered to date. The immunoproteasome hydrophobic residues), the trypsin-like activity (cleavage is optimized to process antigens and it directs the dif- after basic residues), and the caspase-like activity of the ferentiation of T helper (Th) cells. The thymoproteasome proteasome (cleavage after acidic residues). Although the is selectively expressed in cortical epithelial cells of the archaeal and bacterial proteasomes only show chymotryp- thymus where it plays an essential role in the positive sin-like activity, the eukaryotic proteasomes show all three selection of T lymphocytes. Finally, the spermatoprotea- activities that are associated with the b1 (caspase-like some is found in the testes where it is required during activity), b2 (trypsin-like activity), and b5 (chymotryp- spermatogenesis. Here, we outline how tissue-specific sin-like activity) subunits. These b-type subunits of eukar- proteasomes adapt to functional needs in their respec- yotes have been named according to their position in the b tive tissues and how their selective inhibition may be ring [3] (Figure 1). used to interfere with autoimmune diseases and cancer. Interestingly, for the normal housekeeping function of the proteasome in proteolysis of regulatory or misfolded The proteasome: evolution towards complexity and proteins, this diversification is not necessary. Yeast specialization mutants that only harbor the chymotrypsin-like activity The proteasome is an ancient enzyme that has steadily remained viable [4]. Whether specialized proteasome sub- evolved towards a higher complexity of subunits and reg- units are needed to cope with an enhanced protein degra- ulators while preserving its cylindrical architecture con- dation load is currently debated (see below). However, stituted from four stacked rings. In the archebacterium when looking at the peptide products of the proteasome, Thermoplasma acidophilum, the 20S proteasome consists the cleavage preferences of b1, b2, and b5 make a big of two outer rings with seven copies of a single a-type difference. Proteasome products are used by the immune subunit and two inner rings with seven copies of the same system to enable antigen recognition by T lymphocytes and b-type subunit [1] (Figure 1). In the eubacterial actinomy- proteasomal peptide products may even have as yet un- cete Rhodococcus sp., the 20S proteasome is constructed known signaling functions in spermatogenesis or other from two different a-type and two different b-type subunits aspects of cell biology. The functional specialization of [2], whereas in the eukaryotic yeast Saccharomyces cere- b1, b2, and b5 enables the modification of the cleavage visiae, it consists of seven different a-type and seven preferences of the proteasome by replacing them with different b-type subunits [3]. Proteolysis takes place in inducible or tissue-specific homologs. Next to the b1–b2– the inner chamber of the proteasome formed by the two b b5 containing ‘constitutive’ proteasome, three further pro- rings. Although each of the b subunits of the archebacterial teasome subtypes with differing subunit composition have and eubacterial proteasomes carry peptidolytically active been found: the immunoproteasome, the thymoprotea- centers, only three of the seven eukaryotic b-type subunits some, and the spermatoproteasome (Figure 2). Recent are catalytically active. It appears that the increase insights, such as how their special subunit composition in complexity is accompanied with a reduction in the enables them to serve functions that the constitutive pro- number of active b subunits; the driving force for which teasome can only exert suboptimally, are discussed in this has remained elusive. This tendency goes along with a review. The immunoproteasome in antigen processing The immunoproteasome is a tissue-specific complex be- cause it is continuously expressed in cells of the immune system such as T cells, B cells, monocytes, macrophages, dendritic cells, or medullary thymic epithelial cells [5]. However, it is also strongly inducible by the proinflamma- tory cytokines interferon (IFN)-g and tumor necrosis factor (TNF)-a in virtually all tissues except for the brain, where 17 Konstanzer Online-Publikations-System (KOPS) URL: http://nbn-resolving.de/urn:nbn:de:bsz:352-283246 (A) (B) (C) α6 α7 α5 α 1 α4 α α 2 α1 α2 α3 β1 β5 β β2 β β2 β 1 β3 4 β7 β4 β β 2 β1 β6 β5 α7 α3 α α α α 1 α2 6 α5 4 Archaebacterial proteasome Bacterial proteasome Eukaryoc proteasome (acnomycetales) TiBS Figure 1. The proteasome in three kingdoms of life. 20S proteasome models in the barrel-shaped a1–7–1–7b1–7a1–7 pattern. (A) Proteasome from archaebacterium Thermoplasma acidophilum. The archaebacterial proteasome is composed of two outer and two inner rings; each of which contains seven identical a subunits (in red) or b subunit (gray), respectively. (B) Among bacteria, proteasomes have been found in eubacterial actinomycetales. The proteasome from Rhodococcus erythropolis is built of two different a (red and orange) and two different b subunits (gray and green), which are most likely randomly arranged in the respective a and b rings. (C) Proteasome from the eukaryote Saccharomyces cerevisiae. Seven different a and seven different b subunits have their defined positions in the eukaryotic 20S proteasome. immunoproteasome expression is largely confined to to the cell surface. There, the antigen receptor of cytotoxic microglia and invading leukocytes [6]. Remarkably, immu- T lymphocytes can recognize peptide plus MHC and kill the noproteasomes replace up to 90% of constitutive protea- cell that presents their cognate antigens. The criteria for somes in tissues in the course of viral, bacterial, or fungal tight peptide–class I binding are (i) a length of 8–9 amino infections [5–7], which raises the question why the immune acids and (ii) the presence of anchor residues at the C system induces such an extensive change in proteasome terminus of the peptide and somewhere else within the composition. Interestingly, this argues that immunopro- peptide sequence. The C-terminal anchor residues in teasomes can take over the housekeeping functions of humans can be of basic or hydrophobic nature, whereas constitutive proteasomes for several days without harming mouse class I molecules only accept peptides with hydro- the inflamed tissues. phobic C termini. These rather tight acceptance criteria In the immunoproteasome all three active site bearing render it difficult to cleave out a sufficient number of subunits of the constitutive 20S proteasome (b1, b2, and b5) peptide ligands to mount an immune response especially are replaced by homologous, cytokine-inducible subunits against small viruses that encode only a few proteins. It is named b1i [low molecular mass polypeptide (LMP)2], b2i certainly one of the contributions of the immunoprotea- [(multicatalytic endopeptidase complex-like-1 (MECL-1)], some to a successful cellular immune response against and b5i (LMP7), respectively. Two subunits of the immu- viruses or intracellular bacteria that its altered cleavage noproteasome, b1i and b5i, were discovered during genomic priorities enhance the versatility of antigen processing and sequencing of the major histocompatibility complex (MHC) the chance to generate a pivotal antigenic peptide [8]. gene locus over two decades ago, whereas the b2i subunit The recently reported high-resolution X-ray crystallo- was discovered later because it is not encoded in the MHC graphic structures of the mouse constitutive proteasome locus [8]. Many members of the MHC class I and II antigen and immunoproteasome allow a side by side comparison of presentation processing pathways are encoded within the the three different substrate-binding pockets that define MHC locus, which had focused immunoproteasome research the cleavage priorities of the two complexes [13]. The most on their role in antigen processing [9]. striking difference is that between b1 and b1i. Although Proteasome activity is required for MHC class I but not the former accommodates peptides with an acidic P1 resi- class II restricted antigen presentation. This was shown due (caspase-like activity), the latter binds peptides with a with broad spectrum proteasome inhibitors that interfered hydrophobic P1 residue. For unknown reasons, the hun- with MHC class I release from the endoplasmic reticulum dreds of allelic variants of mouse and human MHC class (ER) and class I cell surface expression [10–12], whereas I molecules do not accept peptide ligands with acidic the classical MHC class II pathway was barely affected by C-terminal anchor residues. The proteasome is the main them. The proteasome generates