HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity

Qiaozhen Ye; Rebecca K Lau; Ian T Mathews; Erica A Birkholz; Jeramie D Watrous; Camillia S Azimi; Joe Pogliano; Mohit Jain; Kevin D Corbett

doi:10.1016/j.molcel.2019.12.009

HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity

Mol Cell. 2020 Feb 20;77(4):709-722.e7. doi: 10.1016/j.molcel.2019.12.009. Epub 2020 Jan 10.

Authors

Qiaozhen Ye¹, Rebecca K Lau², Ian T Mathews³, Erica A Birkholz⁴, Jeramie D Watrous⁵, Camillia S Azimi¹, Joe Pogliano⁴, Mohit Jain⁶, Kevin D Corbett⁷

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
² Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
³ Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
⁴ Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
⁵ Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁷ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA; Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, CA, USA. Electronic address: kcorbett@ucsd.edu.

Abstract

Bacteria are continually challenged by foreign invaders, including bacteriophages, and have evolved a variety of defenses against these invaders. Here, we describe the structural and biochemical mechanisms of a bacteriophage immunity pathway found in a broad array of bacteria, including E. coli and Pseudomonas aeruginosa. This pathway uses eukaryotic-like HORMA domain proteins that recognize specific peptides, then bind and activate a cGAS/DncV-like nucleotidyltransferase (CD-NTase) to generate a cyclic triadenylate (cAAA) second messenger; cAAA in turn activates an endonuclease effector, NucC. Signaling is attenuated by a homolog of the AAA+ ATPase Pch2/TRIP13, which binds and disassembles the active HORMA-CD-NTase complex. When expressed in non-pathogenic E. coli, this pathway confers immunity against bacteriophage λ through an abortive infection mechanism. Our findings reveal the molecular mechanisms of a bacterial defense pathway integrating a cGAS-like nucleotidyltransferase with HORMA domain proteins for threat sensing through protein detection and negative regulation by a Trip13 ATPase.

Keywords: AAA+ ATPase remodeler; CD-NTase; HORMA domain; abortive infection; bacteriophage immunity; second messenger signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATPases Associated with Diverse Cellular Activities / chemistry
ATPases Associated with Diverse Cellular Activities / metabolism*
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism*
Bacteriophage lambda / physiology
Deoxyribonuclease I / metabolism
Escherichia coli / immunology
Escherichia coli / metabolism
Escherichia coli / virology*
Nucleotidyltransferases / chemistry
Nucleotidyltransferases / metabolism*
Peptides / metabolism
Second Messenger Systems

Substances

Bacterial Proteins
Peptides
Nucleotidyltransferases
Deoxyribonuclease I
ATPases Associated with Diverse Cellular Activities

Abstract

Publication types

MeSH terms

Substances

Grants and funding