Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity.
Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity.
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DOI：
10.1016/j.celrep.2023.112878
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发表时间：
2023-08-29
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
病毒通过水平转移获得宿主基因，并在感染期间表达它们以操纵宿主生物学。一些同源物保留序列同一性，但进化分歧可以掩盖宿主起源。我们使用结构建模比较牛痘病毒蛋白质与后生动物蛋白质组。我们确定牛痘A47 L作为gasdermins的同源物，gasdermins是引起焦亡的刽子手。A47的X射线晶体结构证实了这种同源性，基于细胞的测定显示A47干扰半胱天冬酶功能。我们还确定牛痘C1 L作为一个隐蔽的基因融合事件耦合Bcl-2相关的折叠与pyrin域的产品。C1与炎性小体的成分相关，炎性小体是一种参与细胞质内炎性凋亡的先天免疫传感器，但矛盾的是，它增强了炎性小体的活性，这表明在感染过程中存在差异调节。我们的研究结果表明，结构同源性筛选的能力越来越强，可以揭示病毒从宿主基因中捕获并以独特方式联合收割机结合的具有独特结构域组合的蛋白质。宿主蛋白质的病毒同源物可以通过序列比较而分化得无法识别。Boys等人使用基于AlphaFold的结构比较来鉴定病毒和宿主蛋白之间的同源性。A47是gasdermins的病毒同系物，干扰炎性体活性，而C1是pyrin-Bcl-2融合体，是促炎性的。
Viruses acquire host genes via horizontal transfer and can express them to manipulate host biology during infections. Some homologs retain sequence identity, but evolutionary divergence can obscure host origins. We use structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identify vaccinia A47L as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirms this homology, and cell-based assays reveal that A47 interferes with caspase function. We also identify vaccinia C1L as the product of a cryptic gene fusion event coupling a Bcl-2-related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting differential modulation during infections. Our findings demonstrate the increasing power of structural homology screens to reveal proteins with unique combinations of domains that viruses capture from host genes and combine in unique ways. Viral homologs of host proteins can diverge beyond recognition by sequence comparison. Boys et al. use AlphaFold-based structural comparisons to identify homology between virus and host proteins. A47, a viral homolog of gasdermins, interferes with inflammasome activity, while C1, a pyrin-Bcl-2 fusion, is pro-inflammatory.
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影响因子：
32.4
作者：
de Almeida L;Khare S;Misharin AV;Patel R;Ratsimandresy RA;Wallin MC;Perlman H;Greaves DR;Hoffman HM;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.8
作者：
González JM;Esteban M
通讯作者：
Esteban M
影响因子：
64.8
作者：
Ding, Jingjin;Wang, Kun;Shao, Feng
通讯作者：
Shao, Feng