Reversible modification of mitochondrial ADP/ATP translocases by paired Legionella effector proteins.
Reversible modification of mitochondrial ADP/ATP translocases by paired Legionella effector proteins.
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DOI：
10.1073/pnas.2122872119
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发表时间：
2022-06-07
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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线粒体是产生ATP的中心代谢细胞器，在真核细胞功能中起着重要作用，因此成为病原菌操纵的靶标。我们发现，细胞内的细菌病原体，嗜肺军团菌，靶向线粒体ADP/ATP转位酶（ANTs），其功能与线粒体ATP合成。这是通过一对效应蛋白Lpg0080和Lpg0081实现的，它们分别作为ADP核糖基转移酶（ART）和ADP核糖基水解酶（ARH）具有相反的酶活性，在感染时协调调节ANT的化学修饰。我们的结构分析表明，Lpg0081是一个ARH与noncanonical macrodomain，其折叠拓扑结构是不同的，从已知的真核生物，古细菌和细菌蛋白质的典型macrodomain。二磷酸腺苷（ADP）核糖基化是一种可逆的翻译后修饰，参与许多细胞过程的调节。已知来自许多病原菌的原型ADP核糖基转移酶（ART）作为毒素起作用，而其他细菌ART最近才出现。最近的研究表明，细菌也具有作为多聚ADP核糖（ADPr）糖水解酶（PARG）的酶，其逆转多聚ADP核糖基化。然而，细菌如何操纵宿主靶蛋白的协调反应的ARTs和ADPr水解酶（ARHs）仍然难以捉摸。细胞内细菌病原体嗜肺军团菌（Legionella pneumophila）是军团病的病原体，其通过Dot/Icm IV型分泌系统将大量效应蛋白转运至宿主细胞。效应蛋白主要作为酶发挥作用，调节宿主细胞过程以使细菌受益。在这项研究中，我们鉴定了一对L。嗜肺菌效应蛋白Lpg0080和Lpg0081，其分别作为ART和ARH发挥作用。这两种蛋白质被证明协调调节线粒体ADP/三磷酸腺苷（ATP）易位酶（ANT）的酶活性共轭ADPr，并删除它，一个关键的精氨酸残基。Lpg0081和Lpg0081：ADPr复合物的晶体结构表明，Lpg0081是一个macroD型ARH与noncanonical macrodomain，其折叠拓扑结构是惊人的不同，从典型的macrodomain是普遍存在于真核PARG和ARH。结果表明，L. pneumophila已经获得了通过ANT的可逆化学修饰协调操纵线粒体活性的效应子对。
Mitochondria are organelles of the central metabolism that produce ATP and play fundamental roles in eukaryotic cell function and thereby become targets for pathogenic bacteria to manipulate. We found that the intracellular bacterial pathogen, Legionella pneumophila, targets mitochondrial ADP/ATP translocases (ANTs), the function of which is linked to the mitochondrial ATP synthesis. This is achieved by a pair of effector proteins, Lpg0080 and Lpg0081, which have opposing enzymatic activities as an ADP ribosyltransferase (ART) and an ADP ribosylhydrolase (ARH), respectively, coordinately regulating the chemical modification of ANTs upon infection. Our structural analyses indicate that Lpg0081 is an ARH with a noncanonical macrodomain, whose folding topology is distinct from that of the canonical macrodomain of known eukaryotic, archaeal, and bacterial proteins. Adenosine diphosphate (ADP) ribosylation is a reversible posttranslational modification involved in the regulation of numerous cellular processes. Prototype ADP ribosyltransferases (ARTs) from many pathogenic bacteria are known to function as toxins, while other bacterial ARTs have just recently emerged. Recent studies have shown that bacteria also possess enzymes that function as poly-ADP ribose (ADPr) glycohydrolases (PARGs), which reverse poly-ADP ribosylation. However, how bacteria manipulate host target proteins by coordinated reactions of ARTs and ADPr hydrolases (ARHs) remains elusive. The intracellular bacterial pathogen Legionella pneumophila, the causative agent of Legionnaires’ disease, transports a large array of effector proteins via the Dot/Icm type IV secretion system to host cells. The effector proteins, which mostly function as enzymes, modulate host cellular processes for the bacteria’s benefit. In this study, we identified a pair of L. pneumophila effector proteins, Lpg0080 and Lpg0081, which function as an ART and an ARH, respectively. The two proteins were shown to coordinately modulate mitochondrial ADP/adenosine triphosphate (ATP) translocases (ANTs) by their enzymatic activities to conjugate ADPr to, and remove it from, a key arginine residue. The crystal structures of Lpg0081 and the Lpg0081:ADPr complex indicated that Lpg0081 is a macroD-type ARH with a noncanonical macrodomain, whose folding topology is strikingly distinct from that of the canonical macrodomain that is ubiquitously found in eukaryotic PARGs and ARHs. Our results illustrate that L. pneumophila has acquired an effector pair that coordinately manipulate mitochondrial activity via reversible chemical modification of ANTs.
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DOI：
10.1084/jem.158.6.2108
发表时间：
1983-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Horwitz MA
通讯作者：
Horwitz MA
影响因子：
64.8
作者：
Kalayil S;Bhogaraju S;Bonn F;Shin D;Liu Y;Gan N;Basquin J;Grumati P;Luo ZQ;Dikic I
通讯作者：
Dikic I
影响因子：
3.4
作者：
Coers, Joern;Vance, Russell E.;Dietrich, William F.
通讯作者：
Dietrich, William F.
影响因子：
56.9
作者：
COLLIER, RJ;COLE, HA
通讯作者：
COLE, HA
影响因子：
4.8
作者：
Chen, Dawei;Vollmar, Melanie;Ahel, Ivan
通讯作者：
Ahel, Ivan