Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.
Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.
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DOI：
10.1016/j.virusres.2015.10.007
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发表时间：
2016-01-04
期刊：
影响因子：
5
通讯作者：
Chan GC
中科院分区：
文献类型：
--
作者：
Burrer CM;Foight GW;Keating AE;Chan GC
卡波西肉瘤相关疱疹病毒（KSHV）与B细胞淋巴瘤相关，包括原发性渗出性淋巴瘤和多中心Castleman病。KSHV通过调节或模拟抗凋亡Bcl-2蛋白家族来促进细胞存活，从而在B细胞内建立潜伏期。我们以前的BH 3分析，一种功能性测定，评估Bcl-2蛋白对细胞存活的贡献，确定了两种Bcl-2蛋白，细胞Mcl-1和病毒KsBcl-2，作为潜在的线粒体极化的调节剂内潜伏感染的B细胞系，Bcbl-1。在这项研究中，我们使用了两种新的肽抑制剂，在肽库筛选，选择性地结合KsBcl-2（KL 6 -7 Y 4 eK）或KsBcl-2和Mcl-1（MS 1），以破译Mcl-1和KsBcl-2在维持线粒体膜电位的相对贡献。我们发现用KL 6 -7 Y 4 eK和MS 1处理刺激从Bcbl-1细胞分离的线粒体释放类似量的细胞色素c，表明单独抑制KsBcl-2足以在潜伏B细胞感染期间进行线粒体外膜通透性（MOMP）和凋亡。反过来，本研究还鉴定了新型KsBcl-2抑制剂的进一步开发并提供了概念验证，用于通过靶向潜伏感染的B细胞治疗KSHV相关B细胞淋巴瘤。
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.