Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet

Sanghyeon Choi, Youngjin Lee, Shinhye Park, Song Yee Jang, Jongbin Park, Do Won Oh, Su-Man Kim, Tae-Hwan Kim, Ga Seul Lee, Changyi Cho, Byoung Sik Kim, Donghan Lee, Eun-Hee Kim, Hae-Kap Cheong, Jeong Hee Moon, Ji-Joon Song, Jungwon Hwang () and Myung Hee Kim ()
Additional contact information
Sanghyeon Choi: Korea Advanced Institute of Science and Technology (KAIST)
Youngjin Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Shinhye Park: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Song Yee Jang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jongbin Park: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Do Won Oh: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Su-Man Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Tae-Hwan Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ga Seul Lee: KRIBB
Changyi Cho: Ewha Womans University
Byoung Sik Kim: Ewha Womans University
Donghan Lee: Korea Basic Science Institute
Eun-Hee Kim: Korea Basic Science Institute
Hae-Kap Cheong: Korea Basic Science Institute
Jeong Hee Moon: KRIBB
Ji-Joon Song: Korea Advanced Institute of Science and Technology (KAIST)
Jungwon Hwang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Myung Hee Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50650-0

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