Spotlight Publications

A bacterial NLR-related protein recognizes multiple unrelated phage triggers to sense infection

Aaron Whiteley — Tue, 17 Dec 2024 16:00:00 +0000

A bacterial NLR-related protein recognizes multiple unrelated phage triggers to sense infection Aaron Whiteley Tue, 12/17/2024 - 09:00

Emily Kibby , Laurel Robbins , Deep A , Min NK , Lindsay Whalen , Toni Nagy , Freeborn L , Corbett KD , Aaron Whiteley

BioRxiv (2024)

Abstract

Immune systems must rapidly sense viral infections to initiate antiviral signaling and protect the host. Bacteria encode >100 distinct viral (phage) defense systems and each has evolved to sense crucial components or activities associated with the viral lifecycle. Here we used a high-throughput AlphaFold-multimer screen to discover that a bacterial NLR-related protein directly senses multiple phage proteins, thereby limiting immune evasion. Phages encoded as many as 5 unrelated activators that were predicted to bind the same interface of a C-terminal sensor domain. Genetic and biochemical assays confirmed activators bound to the bacterial NLR-related protein at high affinity, induced oligomerization, and initiated signaling. This work highlights how in silico strategies can identify complex protein interaction networks that regulate immune signaling across the tree of life.

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Citation

Emily M. Kibby, Laurel K. Robbins, Amar Deep, Nathan K. Min, Lindsay A. Whalen, Toni A. Nagy, Layla Freeborn, Kevin D. Corbett, Aaron T. Whiteley. A bacterial NLR-related protein recognizes multiple unrelated phage triggers to sense infection. bioRxiv 2024.12.17.629029; doi: https://doi.org/10.1101/2024.12.17.629029

Kibby EM, Robbins LK, Deep A, Min NK, Whalen LA, Nagy TA, Freeborn L, Corbett KD, ➤Whiteley, AT | BioRxiv 2024

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Review: Conservation and similarity of bacterial and eukaryotic innate immunity

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

Review: 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). PubMed PMID: 38418927; PubMed Central PMCID: PMC11389603.

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.

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Citation

Ledvina HE, Whiteley AT. Conservation and similarity of bacterial and eukaryotic innate immunity. Nat Rev Microbiol. 2024 Jul;22(7):420-434. doi: 10.1038/s41579-024-01017-1. Epub 2024 Feb 28. Review. PubMed PMID: 38418927; PubMed Central PMCID: PMC11389603.

Ledvina, HE, ➤Whiteley, AT | Nature Reviews Microbiology 2024

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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) PubMed PMID: 36755092; PubMed Central PMCID: PMC10292035

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.

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

Ledvina HE, Ye Q, Gu Y, Sullivan AE, Quan Y, Lau RK, Zhou H, Corbett KD, Whiteley AT. An E1-E2 fusion protein primes antiviral immune signalling in bacteria. Nature. 2023 Apr;616(7956):319-325. doi: 10.1038/s41586-022-05647-4. Epub 2023 Feb 8. PubMed PMID: 36755092; PubMed Central PMCID: PMC10292035.

Ledvina HE*, Ye Q*, Gu Y, Sullivan AE, Quan Y, Lau RK, Zhou H, Corbett KD†, ➤Whiteley AT† (*equal contribution, †co-cor. author) | Nature 2023

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Spotlight Publications

A bacterial NLR-related protein recognizes multiple unrelated phage triggers to sense infection

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Review: Conservation and similarity of bacterial and eukaryotic innate immunity

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

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