Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene

Martinez, Coleen K.; Monaco, John J.

doi:10.1038/353664a0

Cited by 243 publications

(90 citation statements)

References 16 publications

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“…The present studies were undertaken to test whether expression of LMP2 and -7, the two MHC-encoded proteasome subunits (9,10,(16)(17)(18)(19) …”

Section: Introductionmentioning

confidence: 99%

“…Treatment of cells with IEN-y changes the subunit composition of 20S and 26S particles; it induces the addition of new subunits and the loss or modification of several others (15). Two of the new subunits added, LMP2 and -7 (15), are encoded in the MHC region and appear to replace subunits normally present in the 20S particle (16)(17)(18)(19). Moreover, the changes in peptidase activity induced by IFN-y are not seen in a human lymphoblast deletion mutant (line 721.174) lacking 1 megabase of the MHC region (5,20) that includes the LMP2 and -7 genes.…”

mentioning

confidence: 99%

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Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.

Gaczyńska

Rock

Spies

et al. 1994

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

301

215

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Recent studies have implicated proteasomes in the generation ofthe antigenic peptides that are presented on major histocmpatibility complex class I molecules to T lymphocytes. Interferon y modifies the subunit composition of proteasomes and causes changes in their peptidase activities that should favor the production of peptides with hydrophobic or basic carboxyl -termini (i.e., the types found on major histocompatibility complex class I molecules). It has been proposed that these changesIn peptidase activity are due to incorporation into proteasomes of the major histocompatibility complex-encoded subunits.LM1P2 and -7, which are induced by interferon y. Here we show by gene transfection into lymphoblasts or HeLa cells that LMP7 Increases the capacity (V,) of 20S and 26S proteasomes to cleave peptides after hydrophobic and basic residues without, affecting hydrolysis after acidic residues. These changes depended on the amount of LMP7 subunits incorporated into proteasomes. Transfection ofLMP2 reduced cleavage of peptides after acidic residues, increased hydrolysis after basic residues, and did not affect the hydrophobic aciity. Since the activity of the total proteasome population changed after incorporation of only small amounts of LMP2 or -7, these subunits must cause major alterations in peptidase activity. Thus, their expression can account for the changes in proteasome activity induced by interferon 7, and these findings lend further support to the proposed roles of LMPs in altering the nature of the peptides generated for antigen presentation.An initial step in the presentation of intracellular and viral proteins to the immune system is their proteolytic degradation in the cytosol to 8-or 9-residue peptides (1, 2). The antigenic fragments are then taken up into the endoplasmic reticulum, where they associate with the major histocompatibility complex (MHC) class I molecules (3). These peptideprotein complexes are then transported to the cell surface for presentation to cytotoxic T cells (1,3). Recently, strong evidence has been obtained implicating the proteasome (multicatalytic proteinase complex) and the ATP-ubiquitindependent pathway (4) in the process of the generation of antigenic fragments (5-10).The 20S (700 kDa) proteasome particle functions as the proteolytic core of the 26S (1500 kDa) complex that degrades ubiquitin-conjugated proteins (10-13). This particle exhibits multiple peptidase activities, including three well-characterized activities that preferentially hydrolyze small peptides on the carboxyl side of hydrophobic, basic, or acidic residues (10-13). Moreover, these three activities are regulated by the cytokine interferon y (IFN-y), which is a potent stimulator of MHC class I antigen presentation. Treatment of cells with IFN-y does not affect the ability of 20S or 26S particles to degrade model proteins or ubiquitinated proteins but increases their capacity to cleave oligopeptides after hydrophobic and basic residues and reduces cleavage after acidic residues (5-7). These functiona...

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“…The present studies were undertaken to test whether expression of LMP2 and -7, the two MHC-encoded proteasome subunits (9,10,(16)(17)(18)(19) …”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.

Gaczyńska

Rock

Spies

et al. 1994

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

301

215

View full text Add to dashboard Cite

show abstract

“…After infection with virus, processing of viral antigens requires protein degradation by cytoplasmic proteinase into peptides (Kelly et al, 1991 ;Martinez & Monaco, 1991 ;Ortiz-Navarrete et al, 1991) which are subsequently translocated into the endoplasmic reticulum (ER) by ATP-dependent peptide transporters of the ABC family (Powis et al, 1991 ;Spies et al, 1990) or by mechanisms independent of ATP (Levy et al, 1991). In this compartment, the assembly of trimolecular MHC class I complexes involves folding the MHC class I heavy chain (Townsend et al, 1990), transient interaction with chaperonins (Rajagopalan & * Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells

Hengel

Esslinger

Pool

et al. 1995

Journal of General Virology

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CD8 + cytotoxic T cell (CTL) clones with specificity for defined minor and major histocompatibility (H) antigens were used to monitor antigen presentation in human cytomegalovirus (HCMV)-infected skin fibroblasts. At the immediate early stage of virus replication antigen presentation was intact, but was abolished during the early and late phase. Lack of CTL recognition was not selective for certain antigens but was associated with decreased steady state levels of nascent MHC class I complexes and unassembled MHC class I heavy chains, whereas free fl2-microglobulin remained abundant. HCMV also affected the stability of both immature endoglycosidase H (Endo H)-sensitive and mature Endo H-resistant MHC class I molecules, suggesting that the virus interferes with antigen presentation at more than one step during maturation of the MHC class I complex. The action of interferon-y (IFN-7) and tumour necrosis factor-~ (TNF-~) lifted the block of MHC class I complex formation by stimulating synthesis, assembly and stability of MHC class I molecules. This resulted in restored antigen presentation provided that cells were exposed to the factors before HCMV infection. Because few MHC molecules suffice for CTL recognition these cytokines compensated for the negative viral effect on the antigen presentation function. Nevertheless, the viral interference with MHC class I complex formation was still active. The data imply that specific cytokines limit the immune evasion potential of HCMV from CD8 + T lymphocyte control.

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“…Each proteasome has a 20S core, each containing two copies of three distinct proteolytic enzymes. The proteasome exists in two forms: the constitutive proteasome (c20S), expressed ubiquitously throughout the body, and the immunoproteasome (i20S), expressed primarily in haematopoietic cells or in cytokine‐exposed non‐haematopoietic cells (Martinez & Monaco 1991; Glynne et al , 1991, Nandi et al , 1996). In the c20S, proteolytic activities are encoded in the β5, β1 and β2 subunits and are characterized on the basis of substrate specificity as chymotrypsin‐like (CT‐L), caspase‐like and trypsin‐like, respectively.…”

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confidence: 99%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

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Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene

Cited by 243 publications

References 16 publications

Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.

Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.

Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

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