Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.
Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.
复制标题
DOI：
10.1016/j.celrep.2022.110736
复制
发表时间：
2022-04-26
期刊：
影响因子：
8.8
通讯作者：
Matthias, Patrick
中科院分区：
文献类型：
--
作者：
Wang, Longlong;Moreira, Etori Aguiar;Kempf, Georg;Miyake, Yasuyuki;Esteves, Blandina I. Oliveira;Fahmi, Amal;Schaefer, Jonas, V;Dreier, Birgit;Yamauchi, Yohei;Alves, Marco P.;Plueckthun, Andreas;Matthias, Patrick
脱乙酰酶HDAC 6具有串联催化结构域和锌指结构域（ZnF）结合泛素（Ub）。虽然催化结构域具有抗病毒作用，但ZnF促进甲型流感病毒（IAV）感染和细胞应激反应。通过经由ZnF募集Ub，HDAC 6促进侵袭体和应激颗粒（SG）的形成，这是与诸如神经变性的病理相关的动态结构。IAV破坏了侵略者/HDAC 6途径，以促进在早期感染期间的衣壳脱壳。为了靶向这一途径，我们产生了设计的锚蛋白重复序列蛋白（DARPins）结合ZnF;其中之一可以防止在体外和细胞中与Ub相互作用。晶体学分析表明，它阻止了Ub接合的ZnF口袋。这种DARPin的条件性表达可逆地削弱了IAV和寨卡病毒的感染;此外，SG和攻击体被下调。这些结果验证了HDAC 6 ZnF作为药物发现的有吸引力的靶标。一种小的合成蛋白（DARPin）阻断HDAC 6和泛素之间的相互作用。这种DARPin在脱壳步骤中削弱流感病毒和寨卡病毒的感染。两种病毒都含有与其衣壳相关的泛素。DARPin还影响侵袭体和应激颗粒的形成。显示设计的锚蛋白重复蛋白（DARPin F10）靶向HDAC 6锌指结构域阻断其与泛素的相互作用。F10表达削弱流感和寨卡病毒感染以及侵袭体和应激颗粒形成。这突出了HDAC 6介导的泛素募集对于细胞应激反应的重要性。
The deacetylase HDAC6 has tandem catalytic domains and a zinc finger domain (ZnF) binding ubiquitin (Ub). While the catalytic domain has an antiviral effect, the ZnF facilitates influenza A virus (IAV) infection and cellular stress responses. By recruiting Ub via the ZnF, HDAC6 promotes the formation of aggresomes and stress granules (SGs), dynamic structures associated with pathologies such as neurodegeneration. IAV subverts the aggresome/HDAC6 pathway to facilitate capsid uncoating during early infection. To target this pathway, we generate designed ankyrin repeat proteins (DARPins) binding the ZnF; one of these prevents interaction with Ub in vitro and in cells. Crystallographic analysis shows that it blocks the ZnF pocket where Ub engages. Conditional expression of this DARPin reversibly impairs infection by IAV and Zika virus; moreover, SGs and aggresomes are downregulated. These results validate the HDAC6 ZnF as an attractive target for drug discovery. A small synthetic protein (DARPin) blocks interaction between HDAC6 and ubiquitin This DARPin impairs infection by influenza and Zika virus at the uncoating step Both viruses contain ubiquitin associated with their capsid The DARPin also impacts the formation of aggresomes and stress granules Wang et al. show that a designed ankyrin repeat protein (DARPin F10) targeting the HDAC6 zinc finger domain blocks its interaction with ubiquitin. F10 expression impairs influenza and Zika virus infection and aggresomes and stress granules formation. This highlights the importance of HDAC6-mediated ubiquitin recruitment for cellular stress response.
登录
查看更多内容
影响因子：
16.6
作者：
Gestuveo RJ;Royle J;Donald CL;Lamont DJ;Hutchinson EC;Merits A;Kohl A;Varjak M
通讯作者：
Varjak M
影响因子：
5.6
作者：
Binz, HK;Stumpp, MT;Plückthun, A
通讯作者：
Plückthun, A
影响因子：
2.9
作者：
Ash, Peter E. A.;Vanderweyde, Tara E.;Youmans, Katherine L.;Apicco, Daniel J.;Wolozin, Benjamin
通讯作者：
Wolozin, Benjamin
影响因子：
7.3
作者：
de Freitas, Renato Ferreira;Harding, Rachel J.;Schapira, Matthieu
通讯作者：
Schapira, Matthieu
影响因子：
4.6
作者：
Cabantous, Stephanie;Nguyen, Hau B.;Pedelacq, Jean-Denis;Koraichi, Faten;Chaudhary, Anu;Ganguly, Kumkum;Lockard, Meghan A.;Favre, Gilles;Terwilliger, Thomas C.;Waldo, Geoffrey S.
通讯作者：
Waldo, Geoffrey S.