Phosphorylation of caspases by a bacterial kinase inhibits host programmed cell death

• Published in: Nature communications 2024-09, Vol.15 (1), p.8464-14, Article 8464
• Main Authors: Ge, Jinli, Wang, Ying, Li, Xueyu, Lu, Qian, Yu, Hangqian, Liu, Hongtao, Ma, Kelong, Deng, Xuming, Luo, Zhao-Qing, Liu, Xiaoyun, Qiu, Jiazhang
• Format: Article
• Language: English
• Subjects: 631/80/82/23; 631/92/275; 692/699/255/1318; 82/58; 82/80; 82/83; 96/109; 96/2; 96/31; 96/63; Animals; Apoptosis; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Caspase 3 - metabolism; Caspase 7 - metabolism; Caspase-3; Caspase-7; Caspase-9; Caspases - metabolism; Cell death; Cytosol; Effector cells; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Intracellular; Kinases; Legionella pneumophila; Legionella pneumophila - enzymology; Legionella pneumophila - pathogenicity; Legionnaires' Disease - metabolism; Legionnaires' Disease - microbiology; Legionnaires' disease bacterium; Mice; multidisciplinary; Pathogens; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proteolysis; Science; Science (multidisciplinary); Substrates; Virulence factors
• ISSN: 2041-1723; 2041-1723
• 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. The bacterial pathogen Legionella pneumophila delivers hundreds of effector proteins to promote infection. Here, Ge et al show that effector LegK3 suppresses host apoptosis via direct phosphorylation of caspases.