Linear ubiquitination mediates coronavirus NSP14-induced NF-κB activation

作者：Fang Hua, Wenzhuo Hao, Lingyan Wang, Kun Song, Abdul Hasan, Yakun Wu, Kai Way Li, Zhen Lin, Yiwen Sun, Shitao Li · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01949-4 · 被引用次数：8 · 研究领域：interferon and immune responses、NF-κB Signaling Pathways、Phagocytosis and Immune Regulation

Human coronaviruses exhibit a spectrum of symptoms, ranging from mild seasonal colds to severe respiratory manifestations. Despite progress in understanding the host's innate defense mechanisms against coronaviruses, how these viruses manipulate the immune response to promote inflammation remains elusive. In this study, we unveil the role of the coronavirus nonstructural protein 14 (NSP14) in leveraging the host's linear ubiquitin chain assembly complex (LUBAC) to instigate NF-κB activation, thereby triggering proinflammatory responses. Our findings uncover that HOIL-1-interacting protein (HOIP) directly engages with NSP14, conferring linear polyubiquitin chains onto NSP14. Consequently, ubiquitinated NSP14 recruits NEMO and initiates the activation of the IKK complex. This NSP14-induced NF-κB activation stimulates the expression of proinflammatory factors but not type I interferon, leading to a skewed host innate immune response tilting to inflammation. Collectively, our study sheds light on a virus-initiated linear ubiquitination pathway that induces NF-κB signaling and provokes proinflammatory responses.