Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection
Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our pre...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/106146 https://orcid.org/0000-0003-3749-7092 https://orcid.org/0000-0003-4074-8980 |
| _version_ | 1811077955667886080 |
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| author | Burrer, Christine M. Chan, Gary C. Foight, Glenna W. Keating, Amy E. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Burrer, Christine M. Chan, Gary C. Foight, Glenna W. Keating, Amy E. |
| author_sort | Burrer, Christine M. |
| collection | MIT |
| description | Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our previous BH3 profiling analysis, a functional assay that assesses the contribution of Bcl-2 proteins towards cellular survival, identified two Bcl-2 proteins, cellular Mcl-1 and viral KsBcl-2, as potential regulators of mitochondria polarization within a latently infected B-cell line, Bcbl-1. In this study, we used two novel peptide inhibitors identified in a peptide library screen that selectively bind KsBcl-2 (KL6-7_Y4eK) or KsBcl-2 and Mcl-1 (MS1) in order to decipher the relative contribution of Mcl-1 and KsBcl-2 in maintaining mitochondrial membrane potential. We found treatment with KL6-7_Y4eK and MS1 stimulated a similar amount of cytochrome c release from mitochondria isolated from Bcbl-1 cells, indicating that inhibition of KsBcl-2 alone is sufficient for mitochondrial outer membrane permiabilzation (MOMP) and thus apoptosis during a latent B cell infection. In turn, this study also identified and provides a proof-of-concept for the further development of novel KsBcl-2 inhibitors for the treatment of KSHV-associated B-cell lymphomas via the targeting of latently infected B cells. |
| first_indexed | 2024-09-23T10:51:06Z |
| format | Article |
| id | mit-1721.1/106146 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:51:06Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1061462022-09-27T15:27:55Z Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection Burrer, Christine M. Chan, Gary C. Foight, Glenna W. Keating, Amy E. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Foight, Glenna W. Keating, Amy E. Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our previous BH3 profiling analysis, a functional assay that assesses the contribution of Bcl-2 proteins towards cellular survival, identified two Bcl-2 proteins, cellular Mcl-1 and viral KsBcl-2, as potential regulators of mitochondria polarization within a latently infected B-cell line, Bcbl-1. In this study, we used two novel peptide inhibitors identified in a peptide library screen that selectively bind KsBcl-2 (KL6-7_Y4eK) or KsBcl-2 and Mcl-1 (MS1) in order to decipher the relative contribution of Mcl-1 and KsBcl-2 in maintaining mitochondrial membrane potential. We found treatment with KL6-7_Y4eK and MS1 stimulated a similar amount of cytochrome c release from mitochondria isolated from Bcbl-1 cells, indicating that inhibition of KsBcl-2 alone is sufficient for mitochondrial outer membrane permiabilzation (MOMP) and thus apoptosis during a latent B cell infection. In turn, this study also identified and provides a proof-of-concept for the further development of novel KsBcl-2 inhibitors for the treatment of KSHV-associated B-cell lymphomas via the targeting of latently infected B cells. National Institute of General Medical Sciences (U.S.) (Grant GM110048) 2016-12-27T18:54:13Z 2016-12-27T18:54:13Z 2016-01 2015-10 Article http://purl.org/eprint/type/JournalArticle 0168-1702 http://hdl.handle.net/1721.1/106146 Burrer, Christine M. et al. “Selective Peptide Inhibitors of Antiapoptotic Cellular and Viral Bcl-2 Proteins Lead to Cytochrome c Release during Latent Kaposi’s Sarcoma-Associated Herpesvirus Infection.” Virus Research 211 (2016): 86–88. https://orcid.org/0000-0003-3749-7092 https://orcid.org/0000-0003-4074-8980 en_US http://dx.doi.org/10.1016/j.virusres.2015.10.007 Virus Research Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Burrer, Christine M. Chan, Gary C. Foight, Glenna W. Keating, Amy E. Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title | Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title_full | Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title_fullStr | Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title_full_unstemmed | Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title_short | Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi’s sarcoma-associated herpesvirus infection |
| title_sort | selective peptide inhibitors of antiapoptotic cellular and viral bcl 2 proteins lead to cytochrome c release during latent kaposi s sarcoma associated herpesvirus infection |
| url | http://hdl.handle.net/1721.1/106146 https://orcid.org/0000-0003-3749-7092 https://orcid.org/0000-0003-4074-8980 |
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