Abstract
Four proteasome subtypes are commonly present in mammalian tissues: standard proteasomes, which contain the standard catalytic subunits β1, β2 and β5; immunoproteasomes containing the immuno-subunits β1i, β2i and β5i; and two intermediate proteasomes, containing a mix of standard and immuno-subunits. Recent studies revealed the expression of two tissue-specific proteasome subtypes in cortical thymic epithelial cells and in testes: thymoproteasomes and spermatoproteasomes. In this review, we describe the mechanisms that enable the ATP- and ubiquitin-dependent as well as the ATP- and ubiquitin-independent degradation of proteins by the proteasome. We focus on understanding the role of the different proteasome subtypes in maintaining protein homeostasis in normal physiological conditions through the ATP- and ubiquitin-dependent degradation of proteins. Additionally, we discuss the role of each proteasome subtype in the ATP- and ubiquitin-independent degradation of disordered proteins. We also discuss the role of the proteasome in the generation of peptides presented by MHC class I molecules and the implication of having different proteasome subtypes for the peptide repertoire presented at the cell surface. Finally, we discuss the role of the immunoproteasome in immune cells and its modulation as a potential therapy for autoimmune diseases.
Highlights
Protein turnover is essential to maintain appropriate levels of proteins inside cells and to maintain cellular integrity
Proteasomal degradation can take place in an ATP- and ubiquitin-dependent manner. This process of degradation requires the activity of the 26S proteasome, which consist of the 20S proteasome bound to the 19S regulatory particle
Peptides produced following proteasomal degradation can bind major histocompatibility complex (MHC) class I molecules, making the proteasome an important player in allowing the immune system to continuously survey the emergence of abnormal cells
Summary
Protein turnover is essential to maintain appropriate levels of proteins inside cells and to maintain cellular integrity. In infected and transformed cells, some of the peptides presented by MHC class I are derived from viral or tumour-associated proteins and can, activate cytolytic T lymphocytes (CTL), helping the body to eliminate the abnormal cells [3,4] These essential cellular functions make the proteasome a guardian of proteome integrity and a key element in the immunological screening for infected or cancer cells. The promoters of all three immuno-subunit genes contain binding sites for IFN regulatory factor (IRF)-1 transcription factor, conferring responsiveness to IFNγ [45–47] Their promoter regions display binding sites for the nuclear factor kappa B (NF κB) or the cAMP response element binding protein (CREB), which triggers the expression of these inducible subunits after TNF α stimulation or activation of the nitric oxide (NO) signalling pathway, respectively [48–50]. This conformational change might play a role in the functional differences between the β2 and the β2i subunits [53]
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