Spotlight Publications

Conservation and similarity of bacterial and eukaryotic innate immunity

Anonymous — Wed, 28 Feb 2024 21:45:59 +0000

Conservation and similarity of bacterial and eukaryotic innate immunity Anonymous (not verified) Wed, 02/28/2024 - 14:45

Hannah Ledvina Aaron Whiteley

Nat Rev Microbiol (2024). https://doi.org/10.1038/s41579-024-01017-1

Abstract

Pathogens are ubiquitous and a constant threat to their hosts, which has led to the evolution of sophisticated immune systems in bacteria, archaea and eukaryotes. Bacterial immune systems encode an astoundingly large array of antiviral (antiphage) systems, and recent investigations have identified unexpected similarities between the immune systems of bacteria and animals. In this Review, we discuss advances in our understanding of the bacterial innate immune system and highlight the components, strategies and pathogen restriction mechanisms conserved between bacteria and eukaryotes. We summarize evidence for the hypothesis that components of the human immune system originated in bacteria, where they first evolved to defend against phages. Further, we discuss shared mechanisms that pathogens use to overcome host immune pathways and unexpected similarities between bacterial immune systems and interbacterial antagonism. Understanding the shared evolutionary path of immune components across domains of life and the successful strategies that organisms have arrived at to restrict their pathogens will enable future development of therapeutics that activate the human immune system for the precise treatment of disease.

News and Commentaries

Bacterial cGAS-like enzymes produce 2′,3′-cGAMP to activate an ion channel that restricts phage replication

Anonymous — Wed, 26 Jul 2023 16:44:22 +0000

Bacterial cGAS-like enzymes produce 2′,3′-cGAMP to activate an ion channel that restricts phage replication Anonymous (not verified) Wed, 07/26/2023 - 10:44

Uday Tak Peace Holguin-Walth Aaron Whiteley

BioRxiv Preprint, July 24 2023, https://doi.org/10.1101/2023.07.24.550367

Abstract

The mammalian innate immune system uses cyclic GMP–AMP synthase (cGAS) to synthesize the cyclic dinucleotide 2′,3′-cGAMP during antiviral and antitumor immune responses. 2′,3′-cGAMP is a nucleotide second messenger that initiates inflammatory signaling by binding to and activating the stimulator of interferon genes (STING) receptor. Bacteria also encode cGAS/DncV-like nucleotidyltransferases (CD-NTases) that produce nucleotide second messengers to initiate antiviral (antiphage) signaling. Bacterial CD-NTases produce a wide range of cyclic oligonucleotides but have not been documented to produce 2′,3′-cGAMP. Here we discovered bacterial CD-NTases that produce 2′,3′-cGAMP to restrict phage replication. Bacterial 2′,3′-cGAMP binds to CD-NTase associated protein 14 (Cap14), a transmembrane protein of unknown function. Using electrophysiology, we show that Cap14 is a chloride-selective ion channel that is activated by 2′,3′-cGAMP binding. Cap14 adopts a modular architecture, with an N-terminal transmembrane domain and a C-terminal nucleotide-binding SAVED domain. Domain-swapping experiments demonstrated the Cap14 transmembrane region could be substituted with a nuclease, thereby generating a biosensor that is selective for 2′,3′-cGAMP. This study reveals that 2′,3′-cGAMP signaling extends beyond metazoa to bacteria. Further, our findings suggest that transmembrane proteins of unknown function in bacterial immune pathways may broadly function as nucleotide-gated ion channels.

News and Commentaries

Read Uday's Tweetorial [Twitter]

Links

Tak U, Walth P, ➤Whiteley AT | BioRxiv 2023

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Bacterial NLR-related proteins protect against phage

Anonymous — Mon, 08 May 2023 15:17:54 +0000

Bacterial NLR-related proteins protect against phage Anonymous (not verified) Mon, 05/08/2023 - 09:17

Emily Kibby Amy Conte A. Maxwell Burroughs Toni Nagy Alfredo Vargas Lindsay Whalen L. Aravind Aaron Whiteley

Cell (2023). https://doi.org/10.1016/j.cell.2023.04.015

BioRxiv Preprint, July 20 2022, https://www.biorxiv.org/content/10.1101/2022.07.19.500537v1

Abstract

Bacteria use a wide range of immune pathways to counter phage infection. A subset of these genes shares homology with components of eukaryotic immune systems, suggesting that eukaryotes horizontally acquired certain innate immune genes from bacteria. Here, we show that proteins containing a NACHT module, the central feature of the animal nucleotide-binding domain and leucine-rich repeat containing gene family (NLRs), are found in bacteria and defend against phages. NACHT proteins are widespread in bacteria, provide immunity against both DNA and RNA phages, and display the characteristic C-terminal sensor, central NACHT, and N-terminal effector modules. Some bacterial NACHT proteins have domain architectures similar to the human NLRs that are critical components of inflammasomes. Human disease-associated NLR mutations that cause stimulus-independent activation of the inflammasome also activate bacterial NACHT proteins, supporting a shared signaling mechanism. This work establishes that NACHT module-containing proteins are ancient mediators of innate immunity across the tree of life.

News and Commentaries

Ancient mediators of innate immunity [SBGrid]
Cross-kingdom defence proteins [Nature Reviews Microbiology]

An E1–E2 fusion protein primes antiviral immune signalling in bacteria

Anonymous — Thu, 09 Feb 2023 00:00:01 +0000

An E1–E2 fusion protein primes antiviral immune signalling in bacteria Anonymous (not verified) Wed, 02/08/2023 - 17:00

Hannah Ledvina Ye Q Gu Y Ashley Sullivan Quan Y Lau RK Zhou H Corbett KD Aaron Whiteley

Nature (2023). https://doi.org/10.1038/s41586-022-05647-4

Preprint - bioRxiv 2022.03.31.486616; doi: https://doi.org/10.1101/2022.03.31.486616

Abstract

In all organisms, innate immune pathways sense infection and rapidly activate potent immune responses while avoiding inappropriate activation (autoimmunity). In humans, the innate immune receptor cyclic GMP–AMP synthase (cGAS) detects viral infection to produce the nucleotide second messenger cyclic GMP–AMP (cGAMP), which initiates stimulator of interferon genes (STING)-dependent antiviral signalling. Bacteria encode evolutionary predecessors of cGAS called cGAS/DncV-like nucleotidyltransferases (CD-NTases), which detect bacteriophage infection and produce diverse nucleotide second messengers. How bacterial CD-NTase activation is controlled remains unknown. Here we show that CD-NTase-associated protein 2 (Cap2) primes bacterial CD-NTases for activation through a ubiquitin transferase-like mechanism. A cryo-electron microscopy structure of the Cap2–CD-NTase complex reveals Cap2 as an all-in-one ubiquitin transferase-like protein, with distinct domains resembling eukaryotic E1 and E2 proteins. The structure captures a reactive-intermediate state with the CD-NTase C terminus positioned in the Cap2 E1 active site and conjugated to AMP. Cap2 conjugates the CD-NTase C terminus to a target molecule that primes the CD-NTase for increased cGAMP production. We further demonstrate that a specific endopeptidase, Cap3, balances Cap2 activity by cleaving CD-NTase–target conjugates. Our data demonstrate that bacteria control immune signalling using an ancient, minimized ubiquitin transferase-like system and provide insight into the evolution of the E1 and E2 machinery across domains of life.

News and Commentaries

Scientists discover more bacterial tools that could be reprogrammed to treat human disease [CU ��Ƶ Today]

The linguistics of bacterial conflict systems reveal ancient origins of eukaryotic innate immunity

Anonymous — Thu, 19 Nov 2020 15:00:00 +0000

The linguistics of bacterial conflict systems reveal ancient origins of eukaryotic innate immunity Anonymous (not verified) Thu, 11/19/2020 - 08:00

Emily Kibby Aaron Whiteley

J. Bacteriology 2020 Nov 19;202(24):e00507-20. doi: 10.1128/JB.00507-20. Online ahead of print.

Abstract

The arms-race between bacteria and their competitors has produced an astounding variety of conflict systems that are shared via horizontal gene transfer across bacterial populations. In this issue of Journal of Bacteriology, Burroughs and Aravind investigate how these biological conflict systems have been mixed-and-matched into new configurations, often with novel protein domains. The authors additionally characterize the evolutionary history of genes in eukaryotes that appear to have been acquired from these prokaryotic defense systems.

CBASS Immunity Uses CARF-Related Effectors to Sense 3'-5'- and 2'-5'-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection

Anonymous — Thu, 09 Jul 2020 15:00:00 +0000

CBASS Immunity Uses CARF-Related Effectors to Sense 3'-5'- and 2'-5'-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection Anonymous (not verified) Thu, 07/09/2020 - 09:00

Lowey B ➤Whiteley AT Keszei AFA Morehouse BR Mathews IT Antine SP Cabrera VJ Kashin D Niemann P Jain M Schwede F Mekalanos JJ Shao S Lee ASY Kranzusch PJ

Cell. 2020 Jul 9;182(1):38-49.e17. doi: 10.1016/j.cell.2020.05.019. Epub 2020 Jun 15.

Abstract

cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Oligonucleotide recognition occurs through an appended SAVED domain that is an unexpected fusion of two CRISPR-associated Rossman fold (CARF) subunits co-opted from type III CRISPR immunity. Like a lock and key, SAVED effectors exquisitely discriminate 2'-5'- and 3'-5'-linked bacterial cyclicoligonucleotide signals and enable specific recognition of at least 180 potential nucleotide second messenger species. Our results reveal SAVED CARF family proteins as major nucleotide second messenger receptors in CBASS and CRISPR immune defense and extend the importance of linkage specificity beyond mammalian cGAS-STING signaling.

Keywords:

CARF; CBASS antiphage immunity; CD-NTase; SAVED; nucleotide second messenger

Links

PMID: 32544385

DOI: 10.1016/j.cell.2020.05.019

Lowey B, ➤Whiteley AT, Keszei AFA, Morehouse BR, Mathews IT, Antine SP, Cabrera VJ, Kashin D, Niemann P, Jain M, Schwede F, Mekalanos JJ, Shao S, Lee ASY, Kranzusch PJ. | Cell. 2020

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Bacterial cGAS-like enzymes synthesize diverse nucleotide signals

Anonymous — Fri, 01 Mar 2019 07:00:00 +0000

Bacterial cGAS-like enzymes synthesize diverse nucleotide signals Anonymous (not verified) Fri, 03/01/2019 - 00:00

➤Whiteley AT Eaglesham JB de Oliveira Mann CC Morehouse BR Lowey B Nieminen EA Danilchanka O King DS Lee ASY Mekalanos JJ* Kranzusch PJ*

*co-corresponding authors

Nature. 2019 Mar;567(7747):194-199. doi: 10.1038/s41586-019-0953-5. Epub 2019 Feb 20.

Abstract

Cyclic dinucleotides (CDNs) have central roles in bacterial homeostasis and virulence by acting as nucleotide second messengers. Bacterial CDNs also elicit immune responses during infection when they are detected by pattern-recognition receptors in animal cells. Here we perform a systematic biochemical screen for bacterial signalling nucleotides and discover a large family of cGAS/DncV-like nucleotidyltransferases (CD-NTases) that use both purine and pyrimidine nucleotides to synthesize a diverse range of CDNs. A series of crystal structures establish CD-NTases as a structurally conserved family and reveal key contacts in the enzyme active-site lid that direct purine or pyrimidine selection. CD-NTase products are not restricted to CDNs and also include an unexpected class of cyclic trinucleotide compounds. Biochemical and cellular analyses of CD-NTase signalling nucleotides demonstrate that these cyclic di- and trinucleotides activate distinct host receptors and thus may modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts.

News and Commentaries

Pyrimidines and Cyclic Trinucleotides Join the Second Messenger Symphony. [Cell host & microbe 2019]
Diverse bacterial nucleotide signals. [Science Signaling 2019]
Highlighted and discussed in This Week In Microbiology Podcast Episode #206

Links

➤Whiteley AT, Eaglesham JB, de Oliveira Mann CC, Morehouse BR, Lowey B, Nieminen EA, Danilchanka O, King DS, Lee ASY, Mekalanos JJ*, Kranzusch PJ* | Nature. 2019

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