Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales.
Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales.
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作者：
类杆菌利用VI型分泌系统(T6SS)竞争性地在结肠内定植和持续存在。我们鉴定了一个水平转移的T6SS与Nox15家族核酸酶效应器(Tde1)，它介导类杆菌科之间的细菌间拮抗，包括来自单一人类供体的几个。同源(Tdi1)或孤儿免疫蛋白在获得性细菌间防御系统中的表达对Tde1依赖的攻击具有保护作用。我们发现，免疫蛋白的相互作用诱导了TDE核酸酶的大量效应分子构象变化，破坏了活性部位并改变了DNA结合部位。分离的Tde1、Tde1/Tdi1复合体和普通对虾的同源物(Tde2/Tdi2)的晶体快照显示了一种保守的免疫插入TDE中央核心的机制，将核酸酶折叠分裂为两个亚区。TDE/TDI界面和免疫机制不同于所有其他已知结构的多态毒素-免疫相互作用。在先前的研究中，类杆菌的丰度与炎症性肠病的活动有关，我们证明TDE和T6SS结构基因在溃疡性结肠炎受试者的粪便中都富含。类杆菌属中编码T6SS的基因可移动的Tde1介导竞争性生长，并可能参与炎症性肠病。广泛的免疫是由Tdi1同系物通过折叠破坏机制赋予的，这种机制在已知结构的多态效应-免疫对中是独一无二的。类杆菌与炎症性肠病的严重程度和进展有关。我们鉴定了VI型分泌系统(T6SS)核酸酶效应因子(TDE)，它们在溃疡性结肠炎中丰富，并水平转移到可移动的遗传元件上。TDE编码的T6SS介导细菌间竞争。孤儿和同源免疫蛋白(TDI)通过多态毒素系统之间的一种新机制来预防多重TDE中毒。TDI插入效应器中央核心，将Nox15分成两个亚域，扰乱活性部位。这一机制可能允许TDE/TDI界面的进化多样化，如在结肠素核酸酶-免疫相互作用中观察到的那样，促进孤儿TDI对TDE的广泛中和。在溃疡性结肠炎的背景下，依赖TDE的T6SS细菌间拮抗作用可能有助于类杆菌属的多样性。
Bacteroidales use type VI secretion systems (T6SS) to competitively colonize and persist in the colon. We identify a horizontally transferred T6SS with Ntox15 family nuclease effector (Tde1) that mediates interbacterial antagonism among Bacteroidales, including several derived from a single human donor. Expression of cognate (Tdi1) or orphan immunity proteins in acquired interbacterial defense systems protects against Tde1-dependent attack. We find that immunity protein interaction induces a large effector conformational change in Tde nucleases, disrupting the active site and altering the DNA-binding site. Crystallographic snapshots of isolated Tde1, the Tde1/Tdi1 complex, and homologs from Phocaeicola vulgatus (Tde2/Tdi2) illustrate a conserved mechanism of immunity inserting into the central core of Tde, splitting the nuclease fold into two subdomains. The Tde/Tdi interface and immunity mechanism are distinct from all other polymorphic toxin–immunity interactions of known structure. Bacteroidales abundance has been linked to inflammatory bowel disease activity in prior studies, and we demonstrate that Tde and T6SS structural genes are each enriched in fecal metagenomes from ulcerative colitis subjects. Genetically mobile Tde1-encoding T6SS in Bacteroidales mediate competitive growth and may be involved in inflammatory bowel disease. Broad immunity is conferred by Tdi1 homologs through a fold-disrupting mechanism unique among polymorphic effector–immunity pairs of known structure. Bacteroidales are related to inflammatory bowel disease severity and progression. We identify type VI secretion system (T6SS) nuclease effectors (Tde) which are enriched in ulcerative colitis and horizontally transferred on mobile genetic elements. Tde-encoding T6SSs mediate interbacterial competition. Orphan and cognate immunity proteins (Tdi) prevent intoxication by multiple Tde through a new mechanism among polymorphic toxin systems. Tdi inserts into the effector central core, splitting Ntox15 into two subdomains and disrupting the active site. This mechanism may allow for evolutionary diversification of the Tde/Tdi interface as observed in colicin nuclease–immunity interactions, promoting broad neutralization of Tde by orphan Tdi. Tde-dependent T6SS interbacterial antagonism may contribute to Bacteroidales diversity in the context of ulcerative colitis.
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影响因子：
6.4
作者：
Coyne MJ;Zitomersky NL;McGuire AM;Earl AM;Comstock LE
通讯作者：
Comstock LE
影响因子：
7.7
作者：
de Moraes MH;Hsu F;Huang D;Bosch DE;Zeng J;Radey MC;Simon N;Ledvina HE;Frick JP;Wiggins PA;Peterson SB;Mougous JD
通讯作者：
Mougous JD
影响因子：
6.7
作者：
Günther P;Quentin D;Ahmad S;Sachar K;Gatsogiannis C;Whitney JC;Raunser S
通讯作者：
Raunser S
影响因子：
7.7
作者：
Hespanhol JT;Sanchez-Limache DE;Nicastro GG;Mead L;Llontop EE;Chagas-Santos G;Farah CS;de Souza RF;Galhardo RDS;Lovering AL;Bayer-Santos E
通讯作者：
Bayer-Santos E
影响因子：
3.1
作者：
Brodmann M;Schnider ST;Basler M
通讯作者：
Basler M