Department of Bioengineering, Institute for Integrative Genome Biology, School of Medicine, College of Engineering, Biomedical Science, University of California at Riverside, 900 University Avenue, Riverside, CA 92521, USA.
Department of Microbiology, Global Health and Emerging Pathogens Institute, 1468 Madison Avenue, New York, NY 10029, USA.
Viruses. 2022 Feb 3;14(2):314. doi: 10.3390/v14020314.
The identification and elucidation of host pathways for viral infection are critical for understanding the viral infection processes and novel therapeutics development. Here, for the first time, we discover that the human SUMOylation pathway is essential for the IBV viral life cycle. First, IBV viruses were completely inhibited by a novel SUMOylation specific inhibitor, STE025, discovered from our FRET-based high-throughput screening, and the inhibition was very potent, with IC~ 0.1 µM in an IBV-induced cell death rescue assay; Second, we determined that the IBV M1 protein was SUMOylated, which was mediated by the SUMOylation E2 conjugation enzyme and the E3 ligase enzyme at very high affinities, of 0.20 µM and 0.22 µM, respectively; Third, the mutation of the IBV M1 SUMOylation site, K21R, completely abolished the viral particle generation, strongly suggesting the requirement of SUMOylation for the IBV life cycle. These results suggest that the blockage of the host human SUMOylation pathway is very effective for IBV inhibition. We therefore propose that the host SUMOylation pathway is a critical host factor for the IBV virus life cycle. The identification and inhibition of critical host factor(s) provide a novel strategy for future anti-viral therapeutics development, such as IBV and other viruses.
鉴定和阐明宿主病毒感染途径对于理解病毒感染过程和开发新的治疗方法至关重要。在这里，我们首次发现人类 SUMOylation 途径对于 IBV 病毒生命周期是必需的。首先，我们从基于 FRET 的高通量筛选中发现的新型 SUMOylation 特异性抑制剂 STE025 完全抑制了 IBV 病毒，其抑制作用非常有效，在 IBV 诱导的细胞死亡挽救测定中 IC₅₀ 为 0.1 µM；其次，我们确定了 IBV M1 蛋白被 SUMO 化，这是由 SUMOylation E2 连接酶和 E3 连接酶以非常高的亲和力介导的，分别为 0.20 µM 和 0.22 µM；第三，IBV M1 SUMO 化位点 K21R 的突变完全消除了病毒颗粒的产生，强烈表明 SUMO 化对于 IBV 生命周期的要求。这些结果表明阻断宿主人类 SUMOylation 途径对于 IBV 抑制非常有效。因此，我们提出宿主 SUMOylation 途径是 IBV 病毒生命周期的关键宿主因素。鉴定和抑制关键宿主因子为未来抗病毒治疗药物的开发提供了一种新策略，例如 IBV 和其他病毒。
