State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Nat Commun. 2024 Sep 30;15(1):8464. doi: 10.1038/s41467-024-52817-1.
The intracellular bacterial pathogen Legionella pneumophila utilizes the Dot/Icm system to translocate over 330 effectors into the host cytosol. These virulence factors modify a variety of cell processes, including pathways involved in cell death and survival, to promote bacterial proliferation. Here, we show that the effector LegK3 is a eukaryotic-like Ser/Thr kinase that functions to suppress host apoptosis. Mechanistically, LegK3 directly phosphorylates multiple caspases involved in apoptosis signaling, including Caspase-3, Caspase-7, and Caspase-9. LegK3-induced phosphorylation of these caspases occurs at serine (Ser29 in Caspase-3 and Ser199 in Caspase-7) or threonine (Thr102 in Caspase-9) residues located in the prodomain or interdomain linkers. These modifications interfere with the suitability of the caspases as the substrates of initiator caspases or upstream regulators without impacting their proteolytic activity. Collectively, our study reveals a novel strategy used by L. pneumophila to maintain the integrity of infected cells for its intracellular growth.
胞内细菌病原体嗜肺军团菌利用 Dot/Icm 系统将超过 330 种效应蛋白转运到宿主细胞质中。这些毒力因子修饰了多种细胞过程，包括涉及细胞死亡和存活的途径，以促进细菌增殖。在这里，我们表明效应蛋白 LegK3 是一种具有真核样丝氨酸/苏氨酸激酶的功能，可抑制宿主细胞凋亡。在机制上，LegK3 直接磷酸化参与凋亡信号转导的多种半胱天冬酶，包括 Caspase-3、Caspase-7 和 Caspase-9。LegK3 诱导的这些半胱天冬酶的磷酸化发生在位于前导区或结构域间连接区的丝氨酸（Caspase-3 的 Ser29 和 Caspase-7 的 Ser199）或苏氨酸（Caspase-9 的 Thr102）残基上。这些修饰干扰了半胱天冬酶作为起始半胱天冬酶或上游调节剂的底物的适宜性，而不影响它们的蛋白水解活性。总之，我们的研究揭示了嗜肺军团菌用于维持感染细胞完整性以进行其细胞内生长的一种新策略。
