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| Title | Structural and mechanistic insights into the dual-nuclease defense protein Upx as an anti-phage system. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Mar 9, 2026 |
 Authors | Ruimin Zhou / Yingcan Liu / Qian Zhang / Zhenning Yin / Jiajing Tong / Chendi Zhang / Lingling Zhang / Xuzichao Li / Yanhao Zhao / Shuqin Zhang / Zhikun Liu / Weichang Chen / Nan Ji / Heng Zhang / Zhuang Li / Hang Yin / Shengkai Zuo / Yong Wei /  |
| PubMed Abstract | Nucleic acid degradation is a common strategy for prokaryotic anti-phage systems, as exemplified by the CRISPR-Cas system. The PD-(D/E)-XK nucleases constitute a widely distributed family in these ...Nucleic acid degradation is a common strategy for prokaryotic anti-phage systems, as exemplified by the CRISPR-Cas system. The PD-(D/E)-XK nucleases constitute a widely distributed family in these defenses. Notably, most members exhibit a single nuclease domain, while variants containing dual nuclease domains within a single polypeptide remain underexplored, and their molecular mechanisms largely obscure. Here, we biochemically and functionally study a single-protein system containing an uncharacterized PD-(D/E)-XK defense protein (Upx). As revealed by single-particle electron cryo-microscopy (cryo-EM) structure, the C-terminal domain (CTD) harboring the conserved PD-(D/E)XK catalytic core is buttressed by the N-terminal domain (NTD) and the middle domain (MD). Functional assays demonstrate that the nucleic acid binding capability of the CTD is enhanced by the MD. The NTD also displays a noncanonical, basal exonuclease activity that is auto-inhibited by MD. IP-MS experiments identify Upx-interacting phage proteins, and substrate profiling defines its physiological preferences, collectively pointing to its potential physiological targets. Notably, the phage protein gp16 was found to relieve MD-mediated inhibition of the NTD, suggesting a virus-triggered mechanism for activating Upx's dual nuclease activity. Together, these findings establish Upx as a single-protein dual-nuclease anti-phage system, expanding our understanding of bacterial immunity and informing antiviral strategy development. |
 External links | Nat Commun / PubMed:41803127 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.01 Å |
| Structure data | EMDB-66260, PDB-9wuf: |
| Source |
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 Keywords | ANTIVIRAL PROTEIN / protein structure |
Escherichia coli (E. coli)