A bacterial effector SidN/Lpg1083 promotes cell death by targeting Lamin-B2.

To facilitate its survival, replication, and dissemination, the intracellular pathogen Legionella pneumophila relies on its unique Type IVB secretion system (T4SS) to deliver over 330 effectors to hijack host cell pathways in a spatiotemporal manner. The underlying mechanisms of the effectors and their host targets are largely unexplored due to their little sequence identity to known proteins and functional redundancy. The T4SS effector SidN (Lpg1083) is secreted into host cells during the late infection period. However, to the best of our knowledge, the molecular characterization of SidN has not been previously studied. Herein, we identified SidN as a nuclear envelope-localized effector. Its structure adopts a novel fold and the N-terminal domain is crucial for its specific subcellular localization. Furthermore, we found that SidN is transported by the eukaryotic karyopherin Importin-13 into the nucleus, where it attaches to the N-terminal region of Lamin-B2 to interfere with the integrity of the nuclear envelope, causing nuclear membrane disruption and eventually cell death. Our work provides new insights into the structure and function of an L. pneumophila effector protein, and suggests a potential strategy that the pathogen utilizes to promote cell death and then benefit bacterial escape from the host for secondary infection.