Kheimar Ahmed, Trapp-Fragnet Laetitia, Conradie Andelé M, Bertzbach Luca D, You Yu, Sabsabi Mohammad A, Kaufer Benedikt B
Institute of Virology, Freie Universität Berlin , Berlin, Germany.
Department of Poultry Diseases, Faculty of Veterinary Medicine, Sohag University , Sohag, Egypt.
Microbiol Spectr. 2023 Sep 27;11(5):e0188723. doi: 10.1128/spectrum.01887-23.
Human telomerase RNA (hTR) is overexpressed in many cancers and protects T cells from apoptosis in a telomerase-independent manner. The most prevalent cancer in the animal kingdom is caused by the highly oncogenic herpesvirus Marek's disease virus (MDV). MDV encodes a viral telomerase RNA (vTR) that plays a crucial role in MDV-induced tumorigenesis and shares all four conserved functional domains with hTR. In this study, we assessed whether hTR drives tumor formation in this natural model of herpesvirus-induced tumorigenesis. Therefore, we replaced vTR with hTR in the genome of a highly oncogenic MDV. Furthermore, we investigated the anti-apoptotic activity of vTR, hTR, and their counterpart in the chicken [chicken telomerase RNA (cTR)]. hTR was efficiently expressed and did not alter replication of the recombinant virus. Despite its conserved structure, hTR did not complement the loss of vTR in virus-induced tumorigenesis. Strikingly, hTR did not inhibit apoptosis in chicken cells, but efficiently inhibited apoptosis in human cells. Inverse host restriction has been observed for vTR and cTR in human cells. Our data revealed that vTR, cTR, and hTR possess conserved but host-specific anti-apoptotic functions that likely contribute to MDV-induced tumorigenesis. IMPORTANCE hTR is overexpressed in many cancers and used as a cancer biomarker. However, the contribution of hTR to tumorigenesis remains elusive. In this study, we assessed the tumor-promoting properties of hTR using a natural virus/host model of herpesvirus-induced tumorigenesis. This avian herpesvirus encodes a telomerase RNA subunit (vTR) that plays a crucial role in viral tumorigenesis and shares all conserved functional domains with hTR. Our data revealed that vTR and cellular TRs of humans and chickens possess host-specific anti-apoptotic functions. This provides important translational insights into therapeutic strategies, as inhibition of apoptosis is crucial for tumorigenesis.
人类端粒酶RNA（hTR）在许多癌症中过表达，并以一种不依赖端粒酶的方式保护T细胞免于凋亡。动物王国中最常见的癌症是由高度致癌的疱疹病毒马立克氏病病毒（MDV）引起的。MDV编码一种病毒端粒酶RNA（vTR），其在MDV诱导的肿瘤发生中起关键作用，并与hTR共享所有四个保守的功能域。在本研究中，我们评估了hTR是否在这种疱疹病毒诱导的肿瘤发生的天然模型中驱动肿瘤形成。因此，我们在高致癌性MDV的基因组中用hTR替换了vTR。此外，我们研究了vTR、hTR及其在鸡中的对应物[鸡端粒酶RNA（cTR）]的抗凋亡活性。hTR有效表达且不改变重组病毒的复制。尽管其结构保守，但hTR在病毒诱导的肿瘤发生中不能弥补vTR的缺失。令人惊讶的是，hTR不抑制鸡细胞中的凋亡，但能有效抑制人细胞中的凋亡。在人细胞中已观察到vTR和cTR的反向宿主限制。我们的数据表明，vTR、cTR和hTR具有保守但宿主特异性的抗凋亡功能，这可能有助于MDV诱导的肿瘤发生。重要性：hTR在许多癌症中过表达并用作癌症生物标志物。然而，hTR对肿瘤发生的贡献仍不清楚。在本研究中，我们使用疱疹病毒诱导的肿瘤发生的天然病毒/宿主模型评估了hTR的促肿瘤特性。这种禽疱疹病毒编码一种端粒酶RNA亚基（vTR），其在病毒肿瘤发生中起关键作用，并与hTR共享所有保守的功能域。我们的数据表明，人类和鸡的vTR和细胞TR具有宿主特异性的抗凋亡功能。这为治疗策略提供了重要的转化见解，因为抑制凋亡对肿瘤发生至关重要。
