Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China.
Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
J Med Virol. 2024 Oct;96(10):e70007. doi: 10.1002/jmv.70007.
Nuclear factor κB (NF-κB) plays a crucial role in various cellular processes, including inflammatory and immune responses. Its activation is tightly regulated by the IKK (IκB kinase) complex. Upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus is initially recognized by the innate immune system and typically activates the NF-κB pathway, leading to a severe inflammatory response. However, the influence of viral proteins upon pro-inflammatory pathway is complicated. Here, we demonstrated that the viral protein nsp3 of SARS-CoV-2 exhibits an unusual function, which attenuated the NF-κB-mediated inflammatory response against SARS-CoV-2 infection in a unique manner. nsp3 interacted with the essential NF-κB modulator NEMO/IKKγ and promoted its polyubiquitylation via the E3 ubiquitin ligase CBL (Cbl Proto-Oncogene). Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which disrupts NF-κB activation. Moreover, we found that the SARS unique domain (SUD) in nsp3 of SARS-CoV-2 is essential for inducing NEMO degradation, whereas this function is absent in SUD of SARS-CoV. The reduced activation of pro-inflammatory response at an early stage could mask the host immune response and faciliate excessive viral replication. Conversely, this finding may partially explain why SARS-CoV-2 causes a less inflammatory reaction than SARS-CoV, resulting in more mild or moderate COVID-19 cases and greater transmissibility. Given that NEMO is important for NF-κB activation, we propose that inhibiting polyubiquitylation and degradation of NEMO upon SARS-CoV-2 infection is a novel strategy to modulate the host inflammatory response.
核因子 κB（NF-κB）在各种细胞过程中发挥着关键作用，包括炎症和免疫反应。其激活受到 IKK（IκB 激酶）复合物的严格调控。在严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染后，病毒最初被先天免疫系统识别，通常会激活 NF-κB 途径，导致严重的炎症反应。然而，病毒蛋白对促炎途径的影响很复杂。在这里，我们证明了 SARS-CoV-2 的病毒蛋白 nsp3 具有一种不寻常的功能，它以独特的方式减弱了 SARS-CoV-2 感染中 NF-κB 介导的炎症反应。nsp3 与 NF-κB 必需调节剂 NEMO/IKKγ 相互作用，并通过 E3 泛素连接酶 CBL（Cbl 原癌基因）促进其多泛素化。因此，多泛素化的 NEMO 会被蛋白酶体依赖性降解，从而破坏 NF-κB 的激活。此外，我们发现 SARS-CoV-2 的 nsp3 中的 SARS 独特结构域（SUD）对于诱导 NEMO 降解是必不可少的，而 SARS-CoV 的 SUD 则没有这种功能。在早期阶段，促炎反应的激活减少可能会掩盖宿主的免疫反应，并促进病毒的过度复制。相反，这一发现可能部分解释了为什么 SARS-CoV-2 引起的炎症反应比 SARS-CoV 轻，导致 COVID-19 病例更轻微或中度，传染性更强。鉴于 NEMO 对 NF-κB 的激活很重要，我们提出抑制 SARS-CoV-2 感染时 NEMO 的多泛素化和降解是调节宿主炎症反应的一种新策略。
