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TitleA phage-encoded anti-CRISPR protein co-opts host enolase to prevent type III CRISPR immunity.
Journal, issue, pagesNat Microbiol, Vol. 10, Issue 12, Page 3162-3175, Year 2025
Publish dateNov 11, 2025
AuthorsKatie A Johnson / Hemant N Goswami / Ryan J Catchpole / Fozieh Ahmadizadeh / Peng Zhao / Lance Wells / Hong Li / Michael P Terns /
PubMed AbstractCRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems provide powerful adaptive immunity against phage infection. In response, phages use anti-CRISPR (Acr) proteins to evade ...CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems provide powerful adaptive immunity against phage infection. In response, phages use anti-CRISPR (Acr) proteins to evade CRISPR immunity. The few type III Acrs identified so far show conditional effectiveness in countering type III immunity or rely on unknown or poorly understood inhibitory mechanisms. Here we report the discovery of AcrIIIA2, a type III-A Acr encoded by Streptococcus thermophilus phages. Biochemical and structural analyses reveal that phage AcrIIIA2 co-opts host enolase, a highly abundant glycolysis enzyme, to form a ternary complex with the S. thermophilus type III-A (Csm) CRISPR ribonucleoprotein complex, obstructing its immune responses. The enolase-chaperoned AcrIIIA2 blocks the initial step of phage RNA binding, thereby preventing downstream type III anti-phage immune responses. Enolase participates in the anti-immune response by serving as an essential structural scaffold, stabilizing Acr-CRISPR interactions. These findings uncover a new anti-defence strategy that exploits a well-conserved host factor to block CRISPR immunity.
External linksNat Microbiol / PubMed:41219509 / PubMed Central
MethodsEM (single particle)
Resolution2.67 - 2.78 Å
Structure data

49593

9no4

EMDB-49593, PDB-9no4:
Cryo-EM structure of Csm/AcrIIIA2/enolase 3:2 complex
Method: EM (single particle) / Resolution: 2.67 Å

EMDB-49643: Focused map of Csm/AcrIIIA2/enolase 4:3 complex
Method: EM (single particle) / Resolution: 2.78 Å

49645

9nq7

EMDB-49645, PDB-9nq7:
Cryo-EM structure of Csm/AcrIIIA2/enolase 4:3 complex
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-72559: Consensus map of Csm/AcrIIIA2/enolase 3:2 complex
Method: EM (single particle) / Resolution: 2.67 Å

EMDB-72624: Focused map of Csm/AcrIIIA2/enolase 3:2 complex
Method: EM (single particle) / Resolution: 2.72 Å

Chemicals

ChemComp-MG:
Unknown entry

Source
  • streptococcus thermophilus (bacteria)
  • streptococcus phage 2972 (virus)
  • streptococcus phage vb_sths-va214 (virus)
KeywordsRNA BINDING PROTEIN/RNA / ANTI-CRISPR / TYPE III CRISPR / CRYO-EM / STRUCTURAL BIOLOY / ANTI-BACTERIAL / RNA BINDING PROTEIN / RNA BINDING PROTEIN-RNA complex

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