TIR signaling activates caspase-like immunity in bacteria

Science, Journal Year: 2025, Volume and Issue: 387(6733), P. 510 - 516

Published: Jan. 30, 2025

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity regulated cell death humans. We describe a bacterial immune system comprising both caspase-like protease TIR-domain protein. found that the TIR protein, once it recognizes phage invasion, produces previously unknown signaling molecule adenosine 5′-diphosphate-cyclo[N7:1′′]-ribose (N7-cADPR). This specifically activates protease, which then indiscriminately degrades cellular to halt replication. The TIR-caspase defense system, we denote as type IV Thoeris, is abundant bacteria efficiently protects against propagation. Our study highlights diversity of TIR-produced molecules demonstrates by caspase an ancient mechanism immunity.

Language: Английский

---

Chemical inhibition of a bacterial immune system

Published: Feb. 21, 2025

Abstract The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens anti-bacteriophage immune systems that confer to therapeutic phages. Chemical inhibitors these anti-phage could be employed as adjuvants overcome phage-based therapies. Here, we report can selectively inhibited by small molecules, thereby sensitizing phage-resistant We discovered class chemical inhibit the type II Thoeris system. These block biosynthesis histidine-ADPR intracellular ‘alarm’ signal ThsB and prevent ThsA from arresting replication. promiscuously diverse bacteria—including antibiotic-resistant pathogens. inhibition defense improved efficacy model therapy against strain P. aeruginosa mouse infection, suggesting potential. Furthermore, may tools dissect importance system for natural microbial communities.

Language: Английский

---

Advancing RNA phage biology through meta-omics

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(8)

Published: April 22, 2025

Abstract Bacteriophages with RNA genomes are among the simplest biological entities on Earth. Since their discovery in 1960s, they have been used as important models to understand principal processes of life, including translation and genetic code. While phages were generally thought rare oddities nature, meta-omics methods rapidly changing this simplistic view by studying diverse biomes unprecedented resolution. Metatranscriptomics dramatically expanded number known from tens thousands, revealed widespread abundance, discovered several new families potential largely unknown hosts, biology, environmental impact. At same time, (meta)genomic analyses bacterial hosts discovering an arsenal defense systems bacteria employ protect themselves predation, whose functions immunity against we only beginning understand. Here, I review how approaches advancing field phage biology a focus might fight them.

Language: Английский

---

Mechanistic basis for protein conjugation in a diverged bacterial ubiquitination pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Summary Ubiquitination is a fundamental and highly conserved protein post-translational modification pathway, in which ubiquitin or ubiquitin-like (Ubl) typically conjugated to lysine side chain of target protein. multistep process initiated by adenylation the Ubl C-terminus, followed sequential formation 2-3 Ubl∼cysteine thioester intermediates with E1, E2, E3 proteins before final Ubl-lysine isopeptide bond 1 . across eukaryotes, recent work has also revealed at least two related bacterial pathways that perform conjugation context antiphage immunity 2–5 Bioinformatics analysis hinted existence additional, as-yet uncharacterized, bacteria could using ubiquitination-like machinery 6–8 Here we describe architecture biochemical mechanisms Bub ( b acterial ub iquitination-like) pathways, revealing strong structural parallels along striking mechanistic differences when compared eukaryotic ubiquitination pathways. We show operons encode functional are their counterparts but function entirely through oxyester, rather than thioester, intermediates. identify novel family serine proteases serine-histidine catalytic dyad. The genomic suggests that, like other ubiquitination-related they immunity. Overall, our results reveal new unprecedented both deconjugation.

Language: Английский

---

There and back again: Discovering antiviral and antiphage defenses using deep homology

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(9), P. 1466 - 1468

Published: Sept. 1, 2024

Language: Английский

---

Weapon of choice: viruses share cross-kingdom tools

Trends in Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

---