Chapter 3 - Immunoproteasomes: Structure, Function, and Antigen Presentation
Introduction
While the first descriptions of the proteasome were published in the 1970s,1, 2 it was not until the 1990s that the scientific community became aware of a specialized form of the proteasome3, 4, 5, 6 that was later called the immunoproteasome (i-proteasome).7 The name i-proteasome was first given to 20S cores that had incorporated the low-molecular-weight proteins (LMPs) LMP2 and LMP7. These proteins were significantly upregulated in response to the major immunomodulatory cytokine interferon-gamma (IFN-Ī³). An additional factor influencing the choice of name was that the genes encoding LMP2 and LMP7 were located within the major histocompatibility complex (MHC) class II region. The third i-proteasome subunit, the multicatalytic endopeptidase complex subunit 1 (MECL-1), was discovered about a decade later.8, 9, 10 This subunit also responds to IFN-Ī³ stimulation; however, the gene that encodes this protein lies outside the MHC class II region.
Proteasome subtypes are defined by their catalytic subunits. The standard proteasome catalytic subunits include Ī²1, Ī²2, and Ī²5, which are constitutively expressed in all cells. The i-proteasome catalytic subunits, also known as the inducible subunits, are LMP2, MECL-1, and LMP7. An intermediate proteasome containing a mixture of both the standard and i-proteasome subunits has also been described. The most recent proteasome subtype to be discovered is the thymus-specific proteasome, which substitutes the Ī²5 subunit with an alternate protein (Ī²5t).11
The nomenclature for the various proteasome subunits is quite confusing because multiple names have been assigned to each subunit. This is due in part to contributions from multiple laboratories working on different organisms. Table I provides a list of names for the different catalytic subunits and should be a useful reference for future reading, as the nomenclature is not completely standardized. The UniProtKB nomenclature and gene names are also provided to aid in accessing online information. For the purpose of this chapter, we will use the common name for the standard and thymoproteasome subunits (Ī²1, Ī²2, Ī²5, Ī²5t) and the alternate names for the i-proteasome subunits (LMP2, LMP7, MECL-1).
Section snippets
Immunoproteasome Structure
The basic structure of all proteasome subtypes is essentially the same. Each 20S core particle is composed of four stacked rings of seven subunits each. The two outer rings contain the constitutively expressed Ī±-subunits, which interact with regulatory complexes such as PA28 and PA700. The two inner rings contain the Ī²-subunits. Three of the Ī²-subunits in each ring perform distinct proteolytic activities. In the standard proteasome, activity of the catalytic subunits Ī²1, Ī²2, and Ī²5 have been
Regulation of Gene Expression
The two genes that encode LMP2 and LMP7 were first discovered in the early 1980s by Monaco and McDevitt.19, 20 These two genes were subsequently mapped to the MHC class II region, where they are clustered with the TAP-1 and TAP-2 genes. Like LMP2 and LMP7, the expression of TAP proteins is also upregulated by IFN-Ī³. The TAP proteins are transport molecules embedded in the endoplasmic reticulum (ER), where they shuttle peptides destined for MHC class I antigen presentation from the cytoplasm
Assembly of the 20S Core
Assembly of the 20S core is a chaperone-mediated process (reviewed in Ref. 35). The initial step involves the formation of the seven-member ring of Ī±-subunits utilizing dimers of the proteasome-assembling chaperone (PAC1 and PAC2). The PAC1/2 chaperones function as scaffolding and prevent the Ī±-subunits from associating with other nascent Ī±-rings.36 PAC 3 and PAC 4 also assist with Ī±-ring assembly and connect the end subunits together to form the heptameric ring. PAC3/4 also recruits and
Enzymatic Activity
As discussed earlier, the three standard catalytic subunits (Ī²1, Ī²2, Ī²5) perform distinct proteolytic activities. Based on the proteolysis of model peptide substrates, the active sites have been classified as caspase-like, trypsin-like, and chymotrypsin-like for cleavage after acidic, basic, and hydrophobic amino acids, respectively. For the i-proteasome, some differences in catalytic activity and peptide generation have been noted (see discussion in section VII.A). Comparing activity of the Ī²2
Immunoproteasome Knockout Mice
To clarify the physiological role of the i-proteasome subunits, mice deficient in one or more i-proteasome subunits have been generated through the targeted disruption of the gene. These KO mice were developed by immunologists to investigate the putative role of specific i-proteasome subunits in generating immunogenic peptides for antigen presentation. The LMP2ā/ā and LMP7ā/ā strains were developed in 1994 by two different laboratories.46, 47 Development of the MECL-1ā/ā and the thymus-specific
Immunoproteasome Function
The structural and sequence similarities between the standard and i-proteasome cores strongly suggested that the generation of antigenic peptides for MHC class I presentation would be a shared function. A schematic representation of a minimal antigen-processing pathway for MHC class I-restricted epitopes derived from cytosolic proteins is shown in Fig. 3A.55 A representative protein with an epitope (round symbol) is ubiquitinated, targeting the protein to an i-proteasome 20S core. After
Mutations and Linkage to Human Disease
The list of human diseases that have been linked to deregulation of the i-proteasome has grown exponentially over the past decade. However, the data supporting this link are often indirect. For example, increased i-proteasome expression, altered proteasome activity, and/or accumulation of ubiquitinated protein in the diseased tissue have been reported in multiple diseases, including several neurodegenerative diseases of the brain and retina.84, 88, 89 These diseases share oxidation and/or
References (132)
- et al.
A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes
Biochem Biophys Res Commun
(1978) - et al.
The proteasome: paradigm of a self-compartmentalizing protease
Cell
(1998) Degradation of oxidized proteins by the 20S proteasome
Biochimie
(2001)- et al.
Different proteasome subtypes in a single tissue exhibit different enzymatic properties
J Mol Biol
(2000) - et al.
Intermediate-type 20 S proteasomes in HeLa cells: āasymmetricā subunit composition, diversity and adaptation
J Mol Biol
(2007) - et al.
Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities
Mol Cell Proteomics
(2007) - et al.
The LMP antigens: a stable MHC-controlled multisubunit protein complex
Hum Immunol
(1986) - et al.
Genomic organization and tissue expression of mouse proteasome gene Lmp-2
Genomics
(1993) - et al.
Alternative exon usage and processing of the major histocompatibility complex-encoded proteasome subunits
J Biol Chem
(1992) - et al.
DNA sequence, chromosomal localization, and tissue expression of the mouse proteasome subunit lmp10 (Psmb10) gene
Genomics
(1997)
Upregulation of immunoproteasomes by nitric oxide: potential antioxidative mechanism in endothelial cells
Free Radic Biol Med
Beta 2 subunit propeptides influence cooperative proteasome assembly
J Biol Chem
PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome
Am J Hum Genet
Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by dendritic cells: pathway of presentation and regulation by cytokines
Blood
Protein degradation and the generation of MHC class I-presented peptides
Adv Immunol
Altered properties of the branched chain amino acid-preferring activity contribute to increased cleavages after branched chain residues by the āimmunoproteasomeā
J Biol Chem
Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells
Immunity
Thymoproteasome: probable role in generating positively selecting peptides
Curr Opin Immunol
Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules
Mol Cell Proteomics
Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands
Cell
The role of the proteasome activator PA28 in MHC class I antigen processing
Mol Immunol
The N-terminal flanking region of the TRP2360-368 melanoma antigen determines proteasome activator PA28 requirement for epitope liberation
J Biol Chem
Transformation of the proteasome with age-related macular degeneration
FEBS Lett
Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina
Exp Eye Res
Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains
Neurobiol Aging
Role of the proteasome in protein oxidation and neural viability following low-level oxidative stress
FEBS Lett
Altered proteasome function and subunit composition in aged muscle
Arch Biochem Biophys
Alteration of 20S proteasome-subtypes and proteasome activator PA28 in skeletal muscle of rat after induction of diabetes mellitus
Int J Biochem Cell Biol
Potential roles of protein oxidation and the immunoproteasome in MHC class I antigen presentation: the āPrOxIā hypothesis
Arch Biochem Biophys
Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress
Cell
A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes
Proc Natl Acad Sci USA
Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes
Nature
A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC
Nature
Second proteasome-related gene in the human MHC class II region
Nature
Subunit of the ā20Sā proteasome (multicatalytic proteinase) encoded by the major histocompatibility complex
Nature
Interferon-gamma induces different subunit organizations and functional diversity of proteasomes
J Biochem
A third interferon-gamma-induced subunit exchange in the 20S proteasome
Eur J Immunol
The mouse genes encoding the third pair of beta-type proteasome subunits regulated reciprocally by IFN-gamma: structural comparison, chromosomal localization, and analysis of the promoter
J Immunol
Identification of MECL-1 (LMP-10) as the third IFN-gamma-inducible proteasome subunit
J Immunol
Regulation of CD8Ā + T cell development by thymus-specific proteasomes
Science
Comparative resistance of the 20S and 26S proteasome to oxidative stress
Biochem J
Proteasomes in immune cells: more than peptide producers?
Nat Rev Immunol
H-2-linked low-molecular weight polypeptide antigens assemble into an unusual macromolecular complex
Nature
Coordinate regulation of the human TAP1 and LMP2 genes from a shared bidirectional promoter
J Exp Med
How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene
EMBO J
Proteasomes are regulated by interferon gamma: implications for antigen processing
Proc Natl Acad Sci USA
Regulation of the neuronal proteasome by Zif268 (Egr1)
J Neurosci
Genomic organization and tissue expression of the mouse proteasome gene Lmp-7
Immunogenetics
Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma
J Exp Med
Immunoproteasome deficiency alters retinal proteasome's response to stress
J Neurochem
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