Characterization and regulation of the major histocompatibility complex–encoded proteins Hsp70-Hom and Hsp70-1/2

Abstract

Vertebrate cells contain at least 12 different genes for Hsp70 proteins, 3 of which are encoded in the major histocompatibility complex (MHC) class III region. In the human MHC, these are named Hsp70-1, -2, and -Hom. To characterize these proteins, we have determined their substrate binding specificity, their cellular and tissue distribution, and the regulation of their expression. We show for the first time (1) peptide binding specificity of Hsp70-Hom; (2) endogenous expression of Hsp70-Hom in human cell lines; (3) cytoplasmic location of Hsp70-Hom protein under basal conditions and concentration in the nucleus after heat shock; (4) unique RNA expression profiles in human tissues for each of the MHC-encoded Hsp70s, significantly different from that for the constitutive Hsc70; (5) a relative increase in levels of Hsp70-Hom protein, compared with other Hsp70s, in response to interferon gamma; and (6) a specific increase on lipopolysaccharide (LPS) treatment of in vivo messenger RNA levels for the MHC-encoded Hsp70s and the DnaJ homologue, hdj2, relative to other chaperones. The unique tissue distributions and specific up-regulation by LPS of the MHC-encoded Hsp70s suggest some specialization of functions for these members of the Hsp70 family, possibly in the inflammatory response.

Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation

“…We hypothesize a possible role for the differential binding of peptides by heat shock protein-A1L molecules and/or stimulation of cytokines in GVHD. 32 The second SNP marker for grades III-IV acute GVHD, rs394657, resides within the NOTCH4 gene intron and is in positive linkage disequilibrium with nonsynonymous substitutions. Sequence polymorphism of NOTCH4 receptors could influence the inflammatory nature of acute GVHD through altered ligand-receptor binding and production of TNF-a, IFN-g, IL-4, and IL-17.…”

Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

“…The localization of Bip (also known as Hsp70-5 or Grp78) and mtHsp70 (Grp75, Hsp70-9, or mortalin) is confined to the lumen of the endoplasmic reticulum and the mitochondrial matrix, respectively, whereas the remaining six Hsp70 proteins (Table 1) reside mainly in the cytosol, suggesting that they either display specificity for their client proteins or serve chaperone-independent particular functions. Hsc70 (Hsp70-8 or Hsp73) is the only cytosolic Hsp70 protein that is abundantly and ubiquitously expressed in all cells, whereas Hsp70t (Hsp70-Hom or Hsp701L) and Hsp70-2 (HspA2) are expressed at high levels in testis and at considerably lower or nondetectable levels in other tissues (Son et al 1999;Fourie et al 2001). Hsp70-1A and Hsp70-1B are encoded by almost identical intronless genes and are here collectively referred to as Hsp70 (Hsp72 or iHsp70).…”

Enhanced Immunogenicity of Heat Shock Protein 70 Peptide Complexes from Dendritic Cell-Tumor Fusion Cells

“…Human cells contain at least 12 HSP70 genes and we have found that significant levels of 8 different HSP70 family gene products HSP70 -1a, HSP701b, HSP70-HOM, HSP70-4, HSP70-5, HSP70-8, HSP70-9b, HSP75, and HSC70 are expressed in tumor cells (47,48). Three of these (HSP70 -1a, HSP701b, HSP70-HOM) are encoded by genes within the MHC locus suggesting immune function (49).…”