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J J Monaco

Publications and source records attributed to J J Monaco.

At least 55 records · Page 3Linked to original sources
PubMed1993

MHC-linked low-molecular mass polypeptide subunits define distinct subsets of proteasomes. Implications for divergent function among distinct proteasome subsets.

Proteasomes are 650-kDa, multisubunit endopeptidases that might be involved in the MHC class I Ag processing pathway. We demonstrate the existence of multiple structurally distinct subsets of proteasomes. Distinct forms of proteasomes share a hypothetical core to which unique subunits are added. One of these subsets, LMP2+ proteasome, contains the product of the MHC-linked Lmp-2 gene, and can be distinguished serologically and structurally from other proteasome subsets. The expression of LMP2+ and LMP2- proteasomes is variable among cell lines of different tissue types, and their relative abundance and subunit composition are regulated by IFN-gamma. LMP2+ proteasomes comprise 0 to 74% of total cellular proteasomes. Both LMP2+ and LMP2- proteasomes are proteolytically active. We suggest proteasome function might be regulated by subunit composition, and some, or all proteasome subsets, might participate in the production or delivery of peptides to MHC class I molecules. Both LMP2+ and LMP2- subsets can be further subdivided on the basis of the presence or absence of other unique subunits. Implications of the existence of structurally distinct forms of proteasomes in different tissue types is discussed.

Amino Acid Sequence↗
PubMed1993

Post-translational processing of a major histocompatibility complex-encoded proteasome subunit, LMP-2.

Proteasomes are abundant, multisubunit protein complexes found in the cytoplasm and nucleus of eukaryotic cells that catalyze both ubiquitin-dependent and ubiquitin-independent protein degradation. In addition to their role in normal protein turnover, proteasomes are believed to be involved in the production of most antigenic peptides presented to T cells by major histocompatibility complex (MHC) class I molecules. A distinct subset of mouse proteasomes contain a subunit called LMP-2, which is encoded within the MHC. Here we demonstrate that a previously isolated proteasome cDNA clone encodes the LMP-2 subunit, and that two distinct forms of this subunit may be found in the proteasome complex. One form probably corresponds to the primary translation product, whereas the second form appears to be post-translationally processed by removal of the amino-terminal 20 amino acids. Determination of the location of intron/exon boundaries in the Lmp-2 gene indicated that these residues correspond precisely to the first exon of the gene.

Amino Acid Sequence↗
PubMed1993

Structure and function of genes in the MHC class II region.

Genes required for antigen processing map to the MHC class II region. For the endogenous (class I) antigen processing pathway, many hypotheses concerning the structure and function of the corresponding gene products have been verified during the past year. The identity of the gene(s) involved in the exogenous (class II) pathway remains to be determined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Biochemical purification of distinct proteasome subsets.

Proteasomes are intricate cellular proteases that are able to degrade many protein and peptide substrates in vitro. These particles are structurally complex; they are assembled from at least 14 small molecular mass polypeptide subunits to form mature 20S proteasomes. Recently, we demonstrated that proteasome subsets may be discriminated by serological criteria, and have found that subtle differences in the subunit composition of proteasomes can alter their cleavage specificity. Proteasome structural complexity is further enhanced when some proteasomes associate with additional proteins to form a 26S ATP- and ubiquitin-dependent protease. Herein we confirm the existence of distinct cellular forms of proteasomes, and show that they differ in their hydrophobic characteristics. We have reproducibly purified, using solely biochemical techniques, distinct proteasome subsets similar to the serologically defined LMP2+ and LMP2- proteasomes. These proteasome subsets differ in their expression of at least three polypeptides, and both lack several additional polypeptides as compared to the serologically defined LMP2+ and LMP2- proteasomes. Finally, we demonstrate that these structurally unique proteasomes differ in their capacity to cleave a defined panel of fluorogenic peptide substrates. It appears that mammalian cells might recruit and modify proteasomes to perform distinct cellular tasks.

Amino Acid Sequence↗
PubMed1992

T cell recognition of QA-1b antigens on cells lacking a functional Tap-2 transporter.

MHC class Ia H chains and beta 2-microglobulin assemble with appropriate peptides to form stable cell surface molecules that serve as targets for Ag-specific CTL. The structural similarities of class Ia and the less polymorphic Q/T/M (class Ib) molecules suggest that class Ib molecules also play a role in antigen presentation, although the origin of the peptides they present remains mostly unclear. The cell line RMA-S has a defect in class I Ag presentation, presumably due to a mutation in a peptide transporter gene. This defect can be overcome by transfection of RMA-S cells with the Tap-2 gene (formerly Ham-2) that encodes an ATP-binding transporter protein. We now show that a substantial portion of alloreactive CTL specific for Qa-1 class Ib molecules recognize Qa-1b on RMA-S cells and thus differ from most class Ia specific CTL. Those anti-Qa-1b CTL that do not recognize untransfected RMA-S do lyse RMA-S transfected with Tap-2. We also examine the effects of Qdm, a gene that maps to the D region and alters recognition of Qa-1. Qdm(k) strains lack an epitope(s) recognized by some (Qdm dependent) anti-Qa-1 CTL whereas Qdm+ strains express this epitope. Thus, Qdm-dependent CTL do not recognize Qa-1 on Qdm(k) targets whereas Qdm-independent CTL recognize Qa-1 epitopes in all strains. Although Qdm-independent CTL varied as to whether they recognized RMA-S vs RMA, all nine Qdm-dependent clones only recognized Qa-1b on RMA and not RMA-S. This result is consistent with Qdm encoding a peptide dependent upon the TAP transporter for cell membrane expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes.

Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Ham-2 corrects the class I antigen-processing defect in RMA-S cells.

The murine major histocompatibility complex (MHC) contains two genes (Ham-1 and Ham-2) that encode members of a super-family of ATP-dependent transport proteins. These genes are believed to mediate the transport of peptide antigen from the cytoplasm into the lumen of the endoplasmic reticulum for binding by MHC class I molecules. Evidence for such a function has come from the rescue of class I surface expression by a cloned copy of the human homologue of Ham-1, PSF-1, in a human cell line that is defective in antigen processing. A mutant murine cell line, RMA-S, has an identical antigen-processing-defective phenotype. Here we show that expression of a cloned copy of the Ham-2 gene in RMA-S cells results in recovery of the ability to process and present class I-restricted antigens to cytotoxic T lymphocytes, and in partial recovery of class I surface expression. Processing defects for classical (H-2 K and D) and non-classical (Qa1 and HMT) class I molecules are corrected by Ham-2. These data indicate that both MHC-linked transporter genes are probably required for class I antigen processing, and that the functional transporter in this pathway may consist of a Ham-1/Ham-2 heterodimer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Major histocompatibility complex-linked transport proteins and antigen processing.

The major histocompatibility complexes of mice, rats and humans each contain a pair of related genes, Tap-1 and Tap-2, that encode members of a large superfamily of proteins having similar structure and function. The TAP-1 (previously called HAM1 in the mouse) and TAP-2 (HAM2) proteins each contain 6-8 predicted membrane-spanning alpha helices, and a cytoplasmic domain containing a putative ATP-binding site. Recent evidence suggests that a functional TAP-1/TAP-2 heterodimer is required for efficient presentation of antigens to CD8+ cytotoxic T cells. This heterodimer resides in the membrane of the endoplasmic reticulum (ER), and probably functions to transport peptides (produced in the cytoplasm) into the ER lumen for binding to MHC class I molecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

A molecular model of MHC class-I-restricted antigen processing.

Cells of higher vertebrates have evolved mechanisms that allow a sample of their intracellular contents to be available for surveillance by the immune system. This display of intracellular material is in the form of peptides bound to cell surface major histocompatibility complex (MHC) class I molecules. In this review, John Monaco presents a model of the mechanisms by which this takes place, based on the recent identification of a number of new genes in the MHC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Genes in the MHC that may affect antigen processing.

Recent evidence indicates that genes required for antigen processing are present in the class II region of the MHC. Two new classes of MHC genes that may encode much of the machinery required in the class I (endogenous) antigen-processing pathway have been discovered. There is evidence that genes required in the class II pathway also reside in this region.

Animals↗
PubMed1991

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

The class II region of the major histocompatibility complex (MHC) contains genes encoding at least two subunits of a large, intracellular protein complex (the low molecular mass polypeptide, or LMP, complex). This complex is biochemically similar to the proteasome, an abundant and well conserved protein complex having multiple proteolytic activities. Here we report the isolation of a complementary DNA corresponding to one of the subunits of the LMP complex, LMP-2. The protein predicted from this cDNA sequence closely matches the amino-terminal peptide sequence of a rat proteasome subunit, confirming that the proteasome and the LMP complex share polypeptide subunits. The LMP-2 gene is tightly linked to HAM1, a gene thought to be required for translocating peptide fragments of endogenous antigens into the endoplasmic reticulum for association with MHC class I molecules. These observations suggest that the LMP complex may be responsible for generating peptides from cytoplasmic antigen during antigen processing.

Amino Acid Sequence↗
PubMed1991

A new human HLA class II-related locus, DM.

HLA class II molecules have a crucial role in the immune response to antigens. We have isolated two new class II-like complementary DNA sequences, RING6 and RING7, which map between the HLA-DNA and -DOB loci. They are novel members of the immunoglobulin gene family which may have diverged before the duplications that gave rise to the main class II loci. The RING6 and RING7 genes seem to encode alpha- and beta-chains of a previously undiscovered class II-related protein.

Amino Acid Sequence↗
PubMed1991

New class II-like genes in the murine MHC.

Major histocompatibility complex (MHC) class I molecules present endogenous antigens to CD8+ (cytotoxic) T cells. MHC class II molecules present primarily exogenously derived antigens to CD4+ T cells. Three new genes (Ma, Mb1 and Mb2) located between the Pb and Ob genes of the murine MHC have properties indicating that they are members of the MHC class II gene family, but they are the most divergent class II members so far identified and are almost as closely related in sequence to class I genes as they are to the known class II genes.

Amino Acid Sequence↗
PubMed1991

Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes.

Major histocompatibility complex (MHC) class I molecules associate with peptides derived from endogenously synthesized antigens. Cytotoxic T-lymphocytes can thus scan class I molecules and bound peptide on the surface of cells for foreign antigenic determinants. Recent evidence demonstrates that the products of trans-acting, non-class I genes in the class II region of the MHC are required in the class I antigen-processing pathway. There are genes (called HAM1 and HAM2 in the mouse) in this region that encode proteins postulated to be involved in the transport of peptide fragments into the endoplasmic reticulum for association with newly synthesized class I molecules. But, the mechanism by which such peptide fragments are produced remains a mystery. At least two genes encoding subunits of the low-molecular mass polypeptide (LMP) complex are tightly linked to the HAM1 and HAM2 genes. We show that the LMP complex is closely related to the proteasome (multicatalytic proteinase complex), an intracellular protein complex that has multiple proteolytic activities. We speculate that the LMP complex may have a role in MHC class I antigen processing, and therefore that the MHC contains a cluster of genes required for distinct functions in the antigen processing pathway.

Animals↗
PubMed1991

A cluster of transcribed sequences between the Pb and Ob genes of the murine major histocompatibility complex.

The region of the murine major histocompatibility complex (MHC) between the Pb (A beta 3) and Ob (A beta 2) genes controls the expression of an intracellular complex named the LMP (low molecular weight polypeptide) complex. DNA probes for at least seven different genes mapping to this region were isolated. These hybridize to a minimum of eight different transcripts ranging from approximately 1.3 to 3.7 kilobases (kb). The deduced amino acid sequences of the corresponding cDNAs indicate that three of these genes are new members of the MHC class II gene family. These genes are transcribed in a tissue-specific pattern similar to that of the traditional class II genes. Two of the remaining four genes, HAM1 and HAM2, are homologous to one another and to a family of eukaryotic and prokaryotic transport proteins and may be involved in antigen processing. The tissue distribution of HAM1 transcripts is consistent with its proposed role in class I-restricted antigen processing, whereas HAM2 transcription appears more restricted and may be involved in antigen processing for class II-restricted T cells. The HAM2 gene may produce two differentially spliced transcripts. The identity of the remaining two genes is not known. Analyses of transcript sizes, tissue distribution, sequence, and genetic mapping data suggest that none of these genes code for LMP antigens.

Animals↗
PubMed1990

Transport protein genes in the murine MHC: possible implications for antigen processing.

T lymphocyte activation requires recognition by the T cell of peptide fragments of foreign antigen bound to a self major histocompatibility complex (MHC) molecule. Genetic evidence suggests that part of the class II region of the MHC influences the expression, in trans, of MHC class I antigens on the cell surface, by regulating the availability of peptides that bind to and stabilize the class I molecule. Two closely related genes in this region, HAM1 and HAM2, were cloned and had sequence similarities to a superfamily of genes involved in the ATP-dependent transport of a variety of substrates across cell membranes. Thus, these MHC-linked transport protein genes may be involved in transporting antigen, or peptide fragments thereof, from the cytoplasm into a membrane-bounded compartment containing newly synthesized MHC molecules.

Amino Acid Sequence↗