The role of the proteasome in the generation of MHC class I ligands and immune responses

Sijts, Alice J.A.M.; Kloetzel, Peter‐M.

doi:10.1007/s00018-011-0657-y

Cited by 229 publications

(160 citation statements)

References 102 publications

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“…The resulting peptides are transported into the ER through the transporter associated with antigen processing (TAP), where they are loaded onto the awaiting MHC class I molecules by specialized chaperones (24)(25)(26). It is also suggested that some of the MHC peptides are produced by degradation of ER-resident proteins and their signal peptides (27,28).…”

Section: Dripome | Immunopeptidome | Dynamic Silacmentioning

confidence: 99%

The nature and extent of contributions by defective ribosome products to the HLA peptidome

Bourdetsky

Schmelzer

Admon

2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Rapid degradation of newly synthesized proteins, followed by presentation of the resulting peptides by the MHC molecules, serves as an early alert for the immune system during pathogen infection. This study defines the relative contribution to the MHC peptidome of defective ribosome products (DRiPs), which are newly synthesized and rapidly degraded proteins, vs. mature proteins, degraded at the end of their functional lifetimes (retirees). The rates of synthesis of the individual MHC peptides and their source proteins were followed using stable isotope labeling and quantitative proteomics and peptidomics analyses. We conclude that DRiPs are a significant source of MHC peptides. Many of these DRiPs are misassembled surplus subunits of protein complexes and therefore are degraded soon after synthesis.

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Section: Dripome | Immunopeptidome | Dynamic Silacmentioning

confidence: 99%

The nature and extent of contributions by defective ribosome products to the HLA peptidome

Bourdetsky

Schmelzer

Admon

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Further studies using β1i, β2i, or β5i double and/or triple KO mice more convincingly addressed the pivotal roles of these immunosubunits in the production of MHC class I peptides and showed that the immunoproteasome plays a much more important role in antigen presentation than was previously thought. 58,59 A recent surprising discovery established that the immunoproteasome suppresses cell death resulting from IFN-induced oxidative stress by blocking the accumulation of harmful protein aggregates, indicating that the immunoproteasome has unexpected fundamental roles other than a specific role in the production of MHC class I ligands. 60 Efficient clearance of these aggregates by the immunoproteasome helps preserve cell viability under IFN-induced oxidative stress conditions.…”

Section: Immunoproteasomementioning

confidence: 99%

The Proteasome: From Basic Mechanisms to Emerging Roles

Tanaka

2013

Keio J. Med.

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The proteasome is a sophisticated, 2.5-MDa, multisubunit complex that contains a catalytic core particle (CP) and two terminal regulatory particles (RPs); the RPs associate with the termini of the central CP at opposite orientations. The CP consists of four axially stacked heptameric rings (two outer α-rings and two inner β-rings), which are made up of seven structurally related, but not identical, α and β subunits. The CP contains catalytic threonine residues (in β1, β2, and β5 with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the surface of the chamber formed by two abutting β-rings. The RP recognizes polyubiquitylated substrate proteins and unfolds and translocates these proteins to the interior of the CP for degradation. The RP comprises 19 different subunits, which are thought to form two subcomplexes called the lid and the base. One longstanding question is how the complex structure of the proteasome is organized with high fidelity. Recently, we proposed a novel assembly mechanism that is assisted by multiple proteasome-dedicated chaperones. In addition, we discovered two immuno-type proteasomes, the immunoproteasome and the thymoproteasome, whose catalytic subunits are replaced by homologous counterparts. These two isoforms perform specialized functions that help discriminate self from non-self in cell-mediated immunity (i.e., they function as enzymes that process intracellular antigens for cytotoxic T lymphocyte responses and thymic positive selection). Moreover, emerging evidence suggests that the proteasome is crucially involved in the pathophysiology of various intractable diseases that are increasing in today's aging society.

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“…This DRiPs model has been accepted by many different research groups in the field and numerous papers and reviews have described DRiPs as a major source of presented peptides, whereas in contrast, the turnover of mature proteins via the ubiquitin-proteasome pathway has been suggested to play a minor role in generating antigenic peptides (14)(15)(16)(17)(18)(19)(20).…”

Section: Immunology | Virology | Infectionmentioning

confidence: 99%

Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides

Farfán-Arribas

Stern

Rock

2012

Proc. Natl. Acad. Sci. U.S.A.

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All vertebrate nucleated cells generate peptides from their expressed gene products and then display them at the cell surface bound to MHC class I molecules. This allows CD8 + T cells to detect and eliminate abnormal cells that are synthesizing foreign proteins, e.g., from viruses or mutations. To permit the immune system to more uniformly monitor a cell's proteins, regardless of their half-life or location, it has been thought that the products of rapid degradation of the mistakes of protein synthesis (defective ribosomal products, DRiPs) preferentially contribute to the class I-presented peptides. However, using intein catalysis to generate peptide sequences exclusively by posttranslational splicing of mature proteins, we show here that presented peptides can be generated from fully folded and functional proteins. Remarkably, the presentation of peptides from two model mature proteins is just as efficient as from newly synthesized proteins subject to errors in translation or folding. These results indicate that for the constructs we have analyzed, DRiPs are not a more efficient source of class I peptides for antigen presentation than the turnover of mature functional proteins. Accordingly, our data suggest that one of the major ways the immune system evaluates the health of cells is by monitoring the breakdown products of the proteome.

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The role of the proteasome in the generation of MHC class I ligands and immune responses

Cited by 229 publications

References 102 publications

The nature and extent of contributions by defective ribosome products to the HLA peptidome

The nature and extent of contributions by defective ribosome products to the HLA peptidome

The Proteasome: From Basic Mechanisms to Emerging Roles

Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides

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