S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer
Heat shock protein 90 (Hsp90) is a ubiquitous chaperone to interact with numerous proteins to regulate multiple cellular processes, especially during cell proliferation and cell cycle progression. Hsp90 exists in a high level in tumor cells and tissues, and thus serves as a prognostic biomarker or t...
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| Format: | Article |
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Elsevier
2022-11-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722002737 |
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| author | Yu-Yin Shih Hsien-Ya Lin Hau-Ming Jan Yu-Ju Chen Lih-Lih Ong Alice Lin-Tsing Yu Chun-Hung Lin |
| author_facet | Yu-Yin Shih Hsien-Ya Lin Hau-Ming Jan Yu-Ju Chen Lih-Lih Ong Alice Lin-Tsing Yu Chun-Hung Lin |
| author_sort | Yu-Yin Shih |
| collection | DOAJ |
| description | Heat shock protein 90 (Hsp90) is a ubiquitous chaperone to interact with numerous proteins to regulate multiple cellular processes, especially during cell proliferation and cell cycle progression. Hsp90 exists in a high level in tumor cells and tissues, and thus serves as a prognostic biomarker or therapeutic target in cancers. We herein report that Hsp90 is subjected to S-glutathionylation, a redox-dependent modification to form a disulfide bond between the tripeptide glutathione and cysteine residues of proteins, primarily at C366 and C412 in the presence of reactive oxygen species. The modification led to the loss of the ATPase activity. The level of Hsp90 was obviously reduced by S-glutathionylation, owing to C-terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitin proteasome system. S-glutathionylation of Hsp90 was found to crosstalk with its C-terminal phosphorylation of Hsp90 that impedes the binding of Hsp90 with CHIP, demonstrating the importance of chaperone code in modulating Hsp90 function. Further biophysical analyses indicated that S-glutathionylation caused structural change of Hsp90, underlying the aforementioned functional regulation. Moreover, in accordance with the analysis of 64 samples collected from patients of breast cancer, the expression level of Hsp90 inversely correlated with the glutathionylated status of Hsp90. The ratio of total expression to glutathionylated status of Hsp90 was coherent to expression of biomarkers in breast cancer sample, potentiating the prognostic value in the cancer treatment. |
| first_indexed | 2024-04-13T15:43:40Z |
| format | Article |
| id | doaj.art-f0b5b937c5244333901b9d53fc4d651f |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-13T15:43:40Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-f0b5b937c5244333901b9d53fc4d651f2022-12-22T02:41:03ZengElsevierRedox Biology2213-23172022-11-0157102501S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancerYu-Yin Shih0Hsien-Ya Lin1Hau-Ming Jan2Yu-Ju Chen3Lih-Lih Ong4Alice Lin-Tsing Yu5Chun-Hung Lin6x-Dimension Center for Medical Research and Translation, China Medical University Hospital, Taichung, 404332, Taiwan; Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, 11529, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, 11529, TaiwanInstitute of Chemistry, Academia Sinica, Taipei, 11529, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan; Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan; Department of Applied Chemistry at National Yang Ming Chiao Tung University, Hsin-Chu, 30009, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei, 11529, TaiwanInstitute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, 33305, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan; Department of Chemistry and Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan; Corresponding author. Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.Heat shock protein 90 (Hsp90) is a ubiquitous chaperone to interact with numerous proteins to regulate multiple cellular processes, especially during cell proliferation and cell cycle progression. Hsp90 exists in a high level in tumor cells and tissues, and thus serves as a prognostic biomarker or therapeutic target in cancers. We herein report that Hsp90 is subjected to S-glutathionylation, a redox-dependent modification to form a disulfide bond between the tripeptide glutathione and cysteine residues of proteins, primarily at C366 and C412 in the presence of reactive oxygen species. The modification led to the loss of the ATPase activity. The level of Hsp90 was obviously reduced by S-glutathionylation, owing to C-terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitin proteasome system. S-glutathionylation of Hsp90 was found to crosstalk with its C-terminal phosphorylation of Hsp90 that impedes the binding of Hsp90 with CHIP, demonstrating the importance of chaperone code in modulating Hsp90 function. Further biophysical analyses indicated that S-glutathionylation caused structural change of Hsp90, underlying the aforementioned functional regulation. Moreover, in accordance with the analysis of 64 samples collected from patients of breast cancer, the expression level of Hsp90 inversely correlated with the glutathionylated status of Hsp90. The ratio of total expression to glutathionylated status of Hsp90 was coherent to expression of biomarkers in breast cancer sample, potentiating the prognostic value in the cancer treatment.http://www.sciencedirect.com/science/article/pii/S2213231722002737S-glutathionylationHsp90Breast cancerPost-translational modification |
| spellingShingle | Yu-Yin Shih Hsien-Ya Lin Hau-Ming Jan Yu-Ju Chen Lih-Lih Ong Alice Lin-Tsing Yu Chun-Hung Lin S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer Redox Biology S-glutathionylation Hsp90 Breast cancer Post-translational modification |
| title | S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| title_full | S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| title_fullStr | S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| title_full_unstemmed | S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| title_short | S-glutathionylation of Hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| title_sort | s glutathionylation of hsp90 enhances its degradation and correlates with favorable prognosis of breast cancer |
| topic | S-glutathionylation Hsp90 Breast cancer Post-translational modification |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722002737 |
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