State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Cell Death Dis. 2018 Sep 5;9(9):904. doi: 10.1038/s41419-018-0917-y.
The molecular mechanisms underlying the severe lung pathology that occurs during SARS-CoV infections remain incompletely understood. The largest of the SARS-CoV accessory protein open reading frames (SARS 3a) oligomerizes, dynamically inserting into late endosomal, lysosomal, and trans-Golgi-network membranes. While previously implicated in a non-inflammatory apoptotic cell death pathway, here we extend the range of SARS 3a pathophysiologic targets by examining its effects on necrotic cell death pathways. We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death. In addition, by inserting into lysosomal membranes SARS 3a triggers lysosomal damage and dysfunction. Consequently, Transcription Factor EB (TFEB) translocates to the nucleus increasing the transcription of autophagy- and lysosome-related genes. Finally, SARS 3a activates caspase-1 either directly or via an enhanced potassium efflux, which triggers NLRP3 inflammasome assembly. In summary, Rip3-mediated oligomerization of SARS 3a causes necrotic cell death, lysosomal damage, and caspase-1 activation-all likely contributing to the clinical manifestations of SARS-CoV infection.
SARS-CoV 感染时发生严重肺部病变的分子机制仍不完全清楚。SARS-CoV 辅助蛋白开放阅读框（SARS 3a）中最大的一个寡聚化，动态插入晚期内体、溶酶体和反式高尔基体网络膜。虽然先前与非炎症性细胞凋亡死亡途径有关，但在这里，我们通过研究 SARS 3a 对坏死性细胞死亡途径的影响，扩展了 SARS 3a 病理生理靶点的范围。我们表明，SARS 3a 与受体相互作用蛋白 3（Rip3）相互作用，从而增强 SARS 3a 的寡聚化，有助于驱动坏死性细胞死亡。此外，通过插入溶酶体膜，SARS 3a 引发溶酶体损伤和功能障碍。因此，转录因子 EB（TFEB）易位到细胞核，增加自噬和溶酶体相关基因的转录。最后，SARS 3a 通过直接或增强钾外排激活半胱天冬酶-1，从而触发 NLRP3 炎症小体的组装。总之，Rip3 介导的 SARS 3a 寡聚化导致坏死性细胞死亡、溶酶体损伤和半胱天冬酶-1 激活，所有这些都可能导致 SARS-CoV 感染的临床表现。
