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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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 , Burroughs AM , Toni Nagy , Alfredo Vargas , Lindsay Whalen , Aravind L , Aaron Whiteley

Cell (2023). PubMed PMID: 37160116; PubMed Central PMCID: PMC10294775.

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.

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Ancient mediators of innate immunity [SBGrid]
Cross-kingdom defence proteins [Nature Reviews Microbiology]
Read Emily's Tweetorial [Twitter]

Citation

Kibby EM, Conte AN, Burroughs AM, Nagy TA, Vargas JA, Whalen LA, Aravind L, Whiteley AT. Bacterial NLR-related proteins protect against phage. Cell. 2023 May 25;186(11):2410-2424.e18. doi: 10.1016/j.cell.2023.04.015. Epub 2023 May 8. PubMed PMID: 37160116; PubMed Central PMCID: PMC10294775.

Kibby EM, Conte AN, Burroughs AN, Nagy TA, Vargas JA, Whalen LA, Aravind L, ➤Whiteley AT | Cell 2023

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phage defense

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

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Bacterial NLR-related proteins protect against phage

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