Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jamil Mahmud, Brittany W. Geiler, Juthi Biswas, Michael J. Miller, Julia E. Myers, Stephen M. Matthews, Amanda B. Wass, Christine M. O’Connor, Gary C. Chan
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Abstract

Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein–coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.
传入的 HCMV 颗粒输送的 US28 能迅速削弱 Akt 的活性,从而抑制 HCMV 在单核细胞中的溶解复制。
在单核细胞内建立非生产性的静止感染对人类巨细胞病毒(HCMV)的传播至关重要。我们研究了 HCMV 在单核细胞内建立静止感染的机制。US28 是一种病毒编码的 G 蛋白偶联受体(GPCR),对髓系细胞内的静默感染至关重要。我们发现,HCMV 病毒颗粒能迅速将预成形的 US28 运送到单核细胞,而 US28 的重新合成则要延迟数天。缺乏 US28 的重组突变病毒(US28Δ)无法建立静止感染,导致完全生产性的溶解感染,并能产生后代病毒。感染 US28Δ HCMV 后,丝氨酸和苏氨酸激酶 Akt 在 Ser473 和 Thr308 处发生磷酸化,而感染 WT 病毒后,Akt 只在 Ser473 处发生磷酸化。抑制 Akt 的双重磷酸化可阻止 US28Δ 的溶解复制,而异位表达组成型磷酸化 Akt 变体可触发野生型 HCMV 的溶解复制。从机理上讲,我们发现 US28 对于减弱 WT 病毒进入过程中诱导的表皮生长因子受体(EGFR)信号传导是必要且充分的,这导致 Akt 在 Ser473 处发生位点特异性磷酸化。因此,颗粒递送的 US28 通过限制 HCMV 在病毒进入过程中诱导的表皮生长因子受体活化,对 Akt 活性进行了微调,从而使单核细胞中的静止感染得以实现。
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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