Assembly-mediated activation of the SIR2-HerA supramolecular complex for anti-phage defense

Zhangfei Shen; Qingpeng Lin; Xiao-Yuan Yang; Elizabeth Fosuah; Tian-Min Fu

doi:10.1016/j.molcel.2023.11.007

Assembly-mediated activation of the SIR2-HerA supramolecular complex for anti-phage defense

Mol Cell. 2023 Dec 21;83(24):4586-4599.e5. doi: 10.1016/j.molcel.2023.11.007. Epub 2023 Dec 13.

Authors

Zhangfei Shen¹, Qingpeng Lin¹, Xiao-Yuan Yang², Elizabeth Fosuah², Tian-Min Fu³

Affiliations

¹ Department of Biological Chemistry and Pharmacology, The Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
² Department of Biological Chemistry and Pharmacology, The Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Program of OSBP, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Biological Chemistry and Pharmacology, The Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Program of OSBP, The Ohio State University, Columbus, OH 43210, USA. Electronic address: fu.978@osu.edu.

PMID: 38096827
DOI: 10.1016/j.molcel.2023.11.007

Abstract

SIR2-HerA, a bacterial two-protein anti-phage defense system, induces bacterial death by depleting NAD⁺ upon phage infection. Biochemical reconstitution of SIR2, HerA, and the SIR2-HerA complex reveals a dynamic assembly process. Unlike other ATPases, HerA can form various oligomers, ranging from dimers to nonamers. When assembled with SIR2, HerA forms a hexamer and converts SIR2 from a nuclease to an NAD⁺ hydrolase, representing an unexpected regulatory mechanism mediated by protein assembly. Furthermore, high concentrations of ATP can inhibit NAD⁺ hydrolysis by the SIR2-HerA complex. Cryo-EM structures of the SIR2-HerA complex reveal a giant supramolecular assembly up to 1 MDa, with SIR2 as a dodecamer and HerA as a hexamer, crucial for anti-phage defense. Unexpectedly, the HerA hexamer resembles a spiral staircase and exhibits helicase activities toward dual-forked DNA. Together, we reveal the supramolecular assembly of SIR2-HerA as a unique mechanism for switching enzymatic activities and bolstering anti-phage defense strategies.

Keywords: HerA; SIR2; bacterial immunity.

MeSH terms

Adenosine Triphosphatases / genetics
Bacterial Proteins / genetics
Escherichia coli Proteins* / metabolism
Escherichia coli* / enzymology
Escherichia coli* / virology
NAD
Sirtuins* / metabolism
T-Phages*

Substances

Adenosine Triphosphatases
Bacterial Proteins
NAD
Sirtuins
Escherichia coli Proteins