최상현 (KAIST, 한국생명공학원)

한빛사논문

조회155

최상현Sanghyeon Choi

KAIST, 한국생명공학원

Nat. Commun., Jul 23 2024, 15 (1) | https://doi.org/10.1038/s41467-024-50650-0 Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet

Sanghyeon Choi^1,2,11, Youngjin Lee^2,11, Shinhye Park^2,3, Song Yee Jang^2,4, Jongbin Park², Do Won Oh^2,5, Su-Man Kim^2,6, Tae-Hwan Kim^2,7, Ga Seul Lee^4,8, Changyi Cho⁹, Byoung Sik Kim⁹, Donghan Lee¹⁰, Eun-Hee Kim¹⁰, Hae-Kap Cheong¹⁰, Jeong Hee Moon⁴, Ji-Joon Song¹, Jungwon Hwang² & Myung Hee Kim²

¹Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

²Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.

³Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea.

⁴Core Research Facility & Analysis Center, KRIBB, Daejeon 34141, Korea.

⁵Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea.

⁶Department of Biology Education, Chonnam National University, Gwangju 61186, Korea.

⁷College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

⁸College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28644, Korea.

⁹Department of Food Science and Biotechnology, Ewha Womans University, Seoul 03760, Korea.

¹⁰Korea Basic Science Institute, Cheongju, Chungbuk 28119, Korea.

¹¹These authors contributed equally: Sanghyeon Choi, Youngjin Lee.

Corresponding authors

Correspondence to Jungwon Hwang or Myung Hee Kim.

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.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-24)
연구진국내 연구진
분야 생명과학 > 구조생물 및 생물물리학

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