The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection
The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection
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DOI：
10.1073/pnas.2101675118
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发表时间：
2021-08-10
影响因子：
11.1
通讯作者：
Cristea, Ileana M.
中科院分区：
文献类型：
--
作者：
Betsinger, Cora N.;Jankowski, Connor S. R.;Cristea, Ileana M.
病毒在感染期间调节线粒体过程以增加生物合成前体和能量输出，从而为病毒复制提供燃料。令人惊讶的是，虽然它触发线粒体片段化，但流行的病原体人巨细胞病毒（HCMV）通过一种未知的机制增加线粒体代谢。在这里，我们整合分子病毒学，代谢检测，定量蛋白质组学，和超分辨率共聚焦显微镜来定义这种机制。我们确定了以前未表征的病毒蛋白pUL13是生产性HCMV复制所需的，靶向线粒体，并在感染过程中起增加氧化磷酸化的作用。我们证明，pUL13形成时间调谐的相互作用与线粒体接触位点和嵴组织系统（MICOS）复杂，嵴结构和电子传递链（ETC）功能的关键调节器。受激发射损耗超分辨显微镜显示pUL13的表达改变了嵴结构。事实上，使用活细胞Seahorse测定，我们确定pUL13单独足以增加细胞呼吸，而不需要其他病毒蛋白的存在。我们的研究结果解决了HCMV如何靶向线粒体以增加生物能量输出的突出问题，并扩展了线粒体结构和ETC功能之间复杂联系的知识。
Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.