A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC

Abstract

It is now possible to paint a detailed picture of how cytoplasmic proteins are handled by the immune system. They are apparently degraded in the cytoplasm into peptides. These are then transported into the endoplasmic reticulum where they encounter class I major histocompatibility complex (MHC) molecules. Once loaded with peptide, the HLA molecules move through the Golgi apparatus to the cell membrane. Until recently, it had not been established how peptides without signal sequences cross the ER membrane. However, a number of papers have now described a pair of membrane transporter genes of the ABC (ATP-binding cassette) super-family which are attractive candidates for this function. Both transporter genes, which may encode two halves of a heterodimer, are situated in the class II region of the MHC. There is evidence that other putative components of the processing machinery, the LMPs (low molecular mass polypeptides), are also encoded in the MHC. Similarities between the properties of the LMPs and a large intracellular protease complex, called proteasome, have led to the suggestion that LMPs are involved in processing antigens. We have now identified a human gene with sequence homology to proteasome components. Remarkably, this gene maps between the two putative peptide transporter genes.

A Contig Map of theMhcClass I Genomic Region in the Zebrafish Reveals Ancient Synteny

“…In contrast to the situation in the tetrapods, in the zebrafish, a representative of the teleost (bony) fishes, the class I loci are not linked to the class II loci (18), the class II loci are split among three linkage groups (18), and the TAP, as well as the PSMB loci are closely linked to the class I loci (19); in mammals they are located in the class II region (20,21). A survey of different teleost orders indicates that a similar situation to that in the zebrafish exists in other bony fishes (22).…”

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

“…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.…”

Human lymphoblast and erythrocyte multicatalytic proteases: differential peptidase activities and responses to the 11S regulator

“…Association of MCP with the regulatory complex produces the 26S protease which is responsible for ATP-dependent degradation of ubiquitin-conjugated proteins. As part of the larger 26S enzyme, MCP is clearly involved in key cellular functions such as cell cycle traverse and selective intracellular proteolysis (for reviews, see [17][18][19] Two MCP subunits, LMP2 and LMP7, are encoded in the MHC-class II genomic region [20,21], and their expression is upregulated by IFN 7 [22]. These findings suggest that MCP may be involved in the processing of cellular proteins for MHCclass I antigen presentation.…”