Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis, is a major driver of infection; however, the molecular mechanism via which the toxin contributes to septicemia remains unclear. 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.
Competition between bacterial species is a major factor shaping microbial communities. It is possible but remains largely unexplored that competition between bacterial pathogens can be mediated through antagonistic effects of bacterial effector proteins on host systems, particularly the actin cytoskeleton. Using Typhimurium invasion into cells as a model, we demonstrate that invasion is inhibited if the host actin cytoskeleton is disturbed by actin-specific toxins, namely, MARTX actin crosslinking (ACD) and Rho GTPase inactivation (RID) domains, TccC3, and 's own SpvB.
is a Gram-negative, curved, rod-shaped organism that can cause sepsis due to either gastroenteritis when ingested (usually via raw oysters) or skin infections when introduced into cuts or abrasions. Found in estuarine waters (coastal waters where fresh water from streams mixes with salt water from the ocean resulting in water of intermediate salinity (i.e.
MARTX toxins are a type of delivery system found in various Gram-negative bacteria that infect mammals and other animals, but how they target host cells has been unclear.
Researchers identified a specific receptor-binding domain in a MARTX toxin from a dangerous foodborne bacteria, which consists of a 273-amino acid sequence resembling immunoglobulins.
This domain specifically binds to certain sugar structures (N-glycans) on the surface of host cells, making it crucial for the toxin's ability to cause disease during intestinal infections.
Background: () is a deadly opportunistic human pathogen with high mortality worldwide. Notably, climate warming is likely to expand its geographical range and increase the infection risk for individuals in coastal regions. However, due to the absence of comprehensive surveillance systems, the emergence and characteristics of clinical isolates remain poorly understood in China.
The multifunctional autoprocessing repeat-in-toxin (MARTX) toxin is the primary virulence factor of Vibrio vulnificus displaying cytotoxic and hemolytic properties. The cysteine protease domain (CPD) is responsible for activating the MARTX toxin by cleaving the toxin precursor and releasing the mature toxin fragments. To investigate the structural determinants for inositol hexakisphosphate (InsP6)-mediated activation of the CPD, we determined the crystal structures of unprocessed and β-flap truncated MARTX CPDs of Vibrio vulnificus strain MO6-24/O in complex with InsP6 at 1.
