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.
abstract: 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.
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Burrer
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Glenna W
authors.initials: GW
authors.lastname: Foight
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Keating
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, United States. Electronic address: chang@upstate.edu.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000187:drug effects
chemical_list: D010455:Peptides; D014764:Viral Proteins; D019938:Cyclin D1; D045304:Cytochromes c
keywords: B cells; B-cell lymphoma (Bcl)-2; Kaposi's; Latency; Mitochondria; Peptide inhibitors; sarcoma-associated herpesvirus