Department of Dermatology, School of Medicine, University of California Davis (UC Davis), Sacramento, CA 95817, USA.
Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis, Sacramento, CA 95817, USA.
Cell Chem Biol. 2024 Nov 21;31(11):1909-1925.e7. doi: 10.1016/j.chembiol.2024.10.003. Epub 2024 Nov 1.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (K) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.
卡波济肉瘤相关疱疹病毒（KSHV）建立潜伏感染，病毒基因在潜伏染色质中准备转录。在潜伏染色质中，KSHV 潜伏相关核抗原（LANA）与细胞染色质域螺旋酶 DNA 结合蛋白 4（CHD4）相互作用，并抑制病毒启动子激活。CHD4 通过阻止增强子激活启动子来调节细胞分化。在这里，我们从与 LANA-CHD4 相互作用表面相对应的 LANA 序列中鉴定出一种潜在的 CHD4 抑制肽（VGN73）。VGN73 与 CHD4 的 PHD 结构域相互作用，解离常数（K）为 14 nM。用 VGN73 预处理可增强单核细胞向巨噬细胞的分化，并在 U937 细胞中整体改变激活基因的谱。此外，将该肽引入癌细胞中可诱导半胱天冬酶介导的 CHD4 切割，触发细胞死亡，并抑制异种移植小鼠模型中的肿瘤生长。VGN73 可能促进细胞分化治疗。
