Chapter 3 - Immunoproteasomes: Structure, Function, and Antigen Presentation

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Immunoproteasomes contain replacements for the three catalytic subunits of standard proteasomes. In most cells, oxidative stress and proinflammatory cytokines are stimuli that lead to elevated production of immunoproteasomes. Immune system cells, especially antigen-presenting cells, express a higher basal level of immunoproteasomes. A well-described function of immunoproteasomes is to generate peptides with a hydrophobic C terminus that can be processed to fit in the groove of MHC class I molecules. This display of peptides on the cell surface allows surveillance by CD8 T cells of the adaptive immune system for pathogen-infected cells. Functions of immunoproteasomes, other than generating peptides for antigen presentation, are emerging from studies in immunoproteasome-deficient mice, and are complemented by recently described diseases linked to mutations or single-nucleotide polymorphisms in immunoproteasome subunits. Thus, this growing body of literature suggests a more pleiotropic role in cell function for the immunoproteasome.

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 LMP2āˆ’/āˆ’ and LMP7āˆ’/āˆ’ strains were developed in 1994 by two different laboratories.46, 47 Development of the MECL-1āˆ’/āˆ’ 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

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