Thoeris

Contributors: Marie Guillaume, Helena Shomar, Florian Tesson

Description

Thoeris is a two-gene defense system identified in more than 2000 bacterial genomes. It consists of the genes ThsA and thsB. Its anti-phage function was experimentally validated in Bacillus subtilis () . In response to phage infection, it produces an isomer of cyclic ADP-ribose, which leads to the depletion of NAD+ and results in abortive infection.

ThsA contains the sirtuin-like domain which binds to nicotinamide adenine dinucleotide (NAD) metabolites. The N112A point mutation neutralizes the Thoeris defense system and abolishes the NAD+ hydrolase activity of thsA () . It lacks a N-terminal transmembrane domain and is predicted to be cytoplasmic.

ThsB contains a TIR domain () is proposed to participate in the recognition of phage infection, as various thsB proteins sense different phage components.ThsB is found in more than 50% of Thoeris systems in multiple diverse copies () .

Molecular mechanism

The Thoeris system functions by degrading NAD+ (a cofactor of central metabolism) to stop the growth of phage-infected cells and prevent the transmission of the phage to neighboring bacteria () .

The protein ThsB, featuring the TIR domain, plays a crucial role in identifying phage invasion. Upon detecting the infection, the TIR domain becomes enzymatically active, initiating the synthesis of a cADPR isomer molecule () . This molecule acts as a signal, binding to the ThsA effector, likely through its C-terminal SLOG domain, thereby activating its NADase activity () . Consequently, the NADase effector reduces NAD+ cellular levels, creating an environment unsuitable for phage replication (, ) .

Example of genomic structure

The Thoeris is composed of 2 proteins: ThsA and ThsB.

Here is an example found in the RefSeq database:

The Thoeris_I system in Sneathia vaginalis (GCF_000973085.1, NZ_CP011280) is composed of 4 proteins ThsA_new_grand (WP_046328157.1) ThsB_Global (WP_046328158.1) ThsB_Global (WP_052727636.1) ThsB_Global (WP_046328159.1)

Distribution of the system among prokaryotes

Among the 22,803 complete genomes of RefSeq, the Thoeris is detected in 777 genomes (3.41 %).

The system was detected in 298 different species.

Proportion of genome encoding the Thoeris system for the 14 phyla with more than 50 genomes in the RefSeq database.

Structure

Experimentaly determined structure

From () in Bacillus cereus MSX-D12:

Thoeris_I

Example 1

Thoeris_II

Example 1

Experimental validation

      
graph LR;
    Doron_2018[Doron et al., 2018] --> Origin_0
    Origin_0[Bacillus amyloliquefaciens 
AFJ62118.1, AFJ62119.1] --> Expressed_0[Bacillus subtilis]
    Expressed_0[Bacillus subtilis] ----> SPO1 & SBSphiJ & SBSphiC
    Doron_2018[Doron et al., 2018] --> Origin_1
    Ofir_2021[Ofir et al., 2021] --> Origin_1
    Origin_1[Bacillus cereus 
EJR09241.1, EJR09240.1] --> Expressed_1[Bacillus subtilis]
    Expressed_1[Bacillus subtilis] ----> phi29 & SBSphiC & SPO1 & SBSphiJ
    Ofir_2021[Ofir et al., 2021] --> Origin_2
    Origin_2[Bacillus dafuensis 
WP_057775117.1, WP_057775115.1,
WP_057775113.1] --> Expressed_2[Bacillus subtilis]
    Expressed_2[Bacillus subtilis] ----> phi3T & SPBeta & SPR & SBSphi11 & SBSphi13 & phi29 & SBSphiJ & SPO1
    subgraph Title1[Reference]
        Doron_2018
        Ofir_2021
end
    subgraph Title2[System origin]
        Origin_0
        Origin_1
        Origin_1
        Origin_2
end
    subgraph Title3[Expression species]
        Expressed_0
        Expressed_1
        Expressed_1
        Expressed_2
end
    subgraph Title4[Protects against]
        SPO1
        SBSphiJ
        SBSphiC
        phi29
        SBSphiC
        SPO1
        SBSphiJ
        phi29
        SBSphiC
        SPO1
        SBSphiJ
        phi3T
        SPBeta
        SPR
        SBSphi11
        SBSphi13
        phi29
        SBSphiJ
        SPO1
end
    style Title1 fill:none,stroke:none,stroke-width:none
    style Title2 fill:none,stroke:none,stroke-width:none
    style Title3 fill:none,stroke:none,stroke-width:none
    style Title4 fill:none,stroke:none,stroke-width:none

    

References

10.1038/s41586-021-04098-7
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10.1126/science.aar4120
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10.1038/s41467-020-16703-w
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