Two Distinct Pathways Mediated by PA28 and hsp90 in Major Histocompatibility Complex Class I Antigen Processing

Yamano, Toshihisa; Murata, Shigeo; Shimbara, Naoki; Tanaka, Noriaki; Chiba, Tomoki; Tanaka, Keiji; Yui, Katsuyuki; Udono, Heiichiro

doi:10.1084/jem.20011922

Cited by 69 publications

(64 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, short peptides bound to hsp90 which are not to be ubiquitinated are efficiently processed to be T cell epitopes in a proteasome-dependent manner (8). In addition, we found that hsp90 stimulates MHC class I epitope production from C-but not N-terminally extended short synthetic peptides (13 ϳ 22-mer) in a proteasome-dependent manner in vivo (9). Because ubiquitination of those short peptides is unnecessary to be processed by the proteasome, how hsp90 is involved in proteasome-dependent epitope production has still remained elusive.…”

Section: Cd8mentioning

confidence: 61%

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Yamano

Mizukami

Murata

et al. 2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Heat shock protein 90 (hsp90) and the proteasome activator PA28 stimulate major histocompatibility complex (MHC) class I antigen processing. It is unknown whether hsp90 influences the proteasome activity to produce T cell epitopes, although association of PA28 with the 20 S proteasome stimulates the enzyme activity. Here, we show that hsp90 is essential in assembly of the 26 S proteasome and as a result, is involved in epitope production. Addition of recombinant hsp90␣ to cell lysate enhanced chymotrypsinlike activity of the 26 S proteasome in an ATP-dependent manner as determined by an in-gel hydrolysis assay. We successfully pulled down histidine-tagged hsp90␣-and PA28␣-induced, newly assembled 26 S proteasomes from the cell extracts for in vitro epitope production assay, and we found these structures to be sensitive to geldanamycin, an hsp90 inhibitor. We found a cleaved epitope unique to the proteasome pulled down by both hsp90␣ and PA28␣, whereas two different epitopes were identified in the hsp90␣-and PA28␣-pulldowns, respectively. Processing of these respective peptides in vivo was enhanced faithfully by the protein combinations used for the proteasome pulldowns. Inhibition of hsp90 in vivo by geldanamycin partly disrupted the 26 S proteasome structure, consistent with down-regulated MHC class I expression. Our results indicate that hsp90 facilitates MHC class I antigen processing through epitope production in a complex of the 26 S proteasome.

show abstract

Section: Cd8mentioning

confidence: 61%

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Yamano

Mizukami

Murata

et al. 2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other studies have shown that Hsp90 inhibitors suppress MHC class I antigen processing (32). To validate these findings, we show a decrease in the expression of GOLPH2 and MHC class IB proteins by immunohistochemistry (Fig.…”

Section: Itraq-labeled Ms and Gene Expression Microarray Analysismentioning

confidence: 75%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

show abstract

“…Hsp90 has been proposed to be a remnant of an ancient antigen presentation system, and evidence has been presented for its involvement in MHC class I peptide processing and cross-presentation (27)(28)(29). Our results showed that Hsp90 is also required for IFN-␥-induced MHC classes I and II expression.…”

Section: Discussionmentioning

confidence: 99%

The Heat Shock Protein 90-CDC37 Chaperone Complex Is Required for Signaling by Types I and II Interferons

Shang

Tomasi

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Two Distinct Pathways Mediated by PA28 and hsp90 in Major Histocompatibility Complex Class I Antigen Processing

Cited by 69 publications

References 36 publications

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

The Heat Shock Protein 90-CDC37 Chaperone Complex Is Required for Signaling by Types I and II Interferons

Contact Info

Product

Resources

About