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Invasion strategy of pathogenic bacteria is reinforced by a MARTX toxin effector duet

ABSTRACT: Multiple bacterial genera take advantage of the multifunctional utoprocessing repeats-in-toxin (MARTX) toxin to invade host cells1. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis2-5, is a major driver of infection6,7; however, it is not clear how the toxin induces septicemia. Here, we report the crystal and cryo-electron microscopy (EM) structures of a toxin effector duet comprising the domain of unknown function in the first position (DUF1)/Rho inactivation domain (RID) complexed with human targets. These structures reveal how the duet is used by bacteria as a potent weapon. The data show that DUF1 acts as a RID-dependent transforming NADase domain (RDTND) that disrupts NAD+ homeostasis by hijacking calmodulin. The cryo-EM structure of the RDTND-RID duet complexed with calmodulin and Rac1, together with immunological analyses in vitro and in mice, provide mechanistic insight into how V. vulnificus uses the duet to suppress ROS generation by depleting NAD(P)+ and modifying Rac1 in a mutually-reinforcing manner that ultimately paralyzes first line immune responses, promotes dissemination of invaders, and induces sepsis. These data may allow development of tools or strategies to combat MARTX toxin-related human diseases.

INSTRUMENT(S): Orbitrap Exploris 240

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ga Seul Lee

LAB HEAD: Myung Hee Kim

PROVIDER: PXD047927 | Pride | 2024-07-05

REPOSITORIES: Pride

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	20230908SHChoi_IP_01.raw	Raw
	20230908SHChoi_IP_02.raw	Raw
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A transcriptomic study reveals that fish vibriosis due to the zoonotic pathogen Vibrio vulnificus is an acute inflammatory disease.

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