Insights into the modulation of bacterial NADase activity by phage proteins
© 2024. The Author(s)..
The Silent Information Regulator 2 (SIR2) protein is widely implicated in antiviral response by depleting the cellular metabolite NAD+. The defense-associated sirtuin 2 (DSR2) effector, a SIR2 domain-containing protein, protects bacteria from phage infection by depleting NAD+, while an anti-DSR2 protein (DSR anti-defense 1, DSAD1) is employed by some phages to evade this host defense. The NADase activity of DSR2 is unleashed by recognizing the phage tail tube protein (TTP). However, the activation and inhibition mechanisms of DSR2 are unclear. Here, we determine the cryo-EM structures of DSR2 in multiple states. DSR2 is arranged as a dimer of dimers, which is facilitated by the tetramerization of SIR2 domains. Moreover, the DSR2 assembly is essential for activating the NADase function. The activator TTP binding would trigger the opening of the catalytic pocket and the decoupling of the N-terminal SIR2 domain from the C-terminal domain (CTD) of DSR2. Importantly, we further show that the activation mechanism is conserved among other SIR2-dependent anti-phage systems. Interestingly, the inhibitor DSAD1 mimics TTP to trap DSR2, thus occupying the TTP-binding pocket and inhibiting the NADase function. Together, our results provide molecular insights into the regulatory mechanism of SIR2-dependent NAD+ depletion in antiviral immunity.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Nature communications - 15(2024), 1 vom: 27. März, Seite 2692 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yin, Hang [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
0U46U6E8UK |
|---|
| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 30.03.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-024-47030-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370281373 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370281373 | ||
| 003 | DE-627 | ||
| 005 | 20240331001343.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240329s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-024-47030-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1357.xml |
| 035 | |a (DE-627)NLM370281373 | ||
| 035 | |a (NLM)38538592 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yin, Hang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Insights into the modulation of bacterial NADase activity by phage proteins |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.03.2024 | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a The Silent Information Regulator 2 (SIR2) protein is widely implicated in antiviral response by depleting the cellular metabolite NAD+. The defense-associated sirtuin 2 (DSR2) effector, a SIR2 domain-containing protein, protects bacteria from phage infection by depleting NAD+, while an anti-DSR2 protein (DSR anti-defense 1, DSAD1) is employed by some phages to evade this host defense. The NADase activity of DSR2 is unleashed by recognizing the phage tail tube protein (TTP). However, the activation and inhibition mechanisms of DSR2 are unclear. Here, we determine the cryo-EM structures of DSR2 in multiple states. DSR2 is arranged as a dimer of dimers, which is facilitated by the tetramerization of SIR2 domains. Moreover, the DSR2 assembly is essential for activating the NADase function. The activator TTP binding would trigger the opening of the catalytic pocket and the decoupling of the N-terminal SIR2 domain from the C-terminal domain (CTD) of DSR2. Importantly, we further show that the activation mechanism is conserved among other SIR2-dependent anti-phage systems. Interestingly, the inhibitor DSAD1 mimics TTP to trap DSR2, thus occupying the TTP-binding pocket and inhibiting the NADase function. Together, our results provide molecular insights into the regulatory mechanism of SIR2-dependent NAD+ depletion in antiviral immunity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Sirtuins |2 NLM | |
| 650 | 7 | |a EC 3.5.1.- |2 NLM | |
| 650 | 7 | |a Silent Information Regulator Proteins, Saccharomyces cerevisiae |2 NLM | |
| 650 | 7 | |a NAD |2 NLM | |
| 650 | 7 | |a 0U46U6E8UK |2 NLM | |
| 650 | 7 | |a NAD+ Nucleosidase |2 NLM | |
| 650 | 7 | |a EC 3.2.2.5 |2 NLM | |
| 650 | 7 | |a Sirtuin 2 |2 NLM | |
| 650 | 7 | |a EC 3.5.1.- |2 NLM | |
| 650 | 7 | |a Bacterial Proteins |2 NLM | |
| 700 | 1 | |a Li, Xuzichao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoshen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Chendi |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jiaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Guimei |e verfasserin |4 aut | |
| 700 | 1 | |a He, Qiuqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhuang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Heng |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 15(2024), 1 vom: 27. März, Seite 2692 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g day:27 |g month:03 |g pages:2692 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-024-47030-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |e 1 |b 27 |c 03 |h 2692 | ||