Yu Xuekui's team from Shanghai Institute of Medicine explained the molecular mechanism of "pressure sensing and regulation" in the process of herpes virus genome packaging, stabilization and release

Human cytomegalovirus (HCMV) belongs to the β subfamily of the Herpesviridae family and is a double-stranded DNA enveloped virus that spreads widely in humans
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HCMV infection can bring fatal harm to people with low immunity (such as organ transplant patients or AIDS patients).
In addition, it can also cause fetal death and newborn birth defects
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HCMV has a typical herpes virus three-layer structure: the outermost layer is a lipid bilayer envelope containing glycoproteins; the innermost layer is a quasi-icosahedral nucleocapsid containing the dsDNA genome; the outer layer Between the envelope and the inner nucleocapsid is a tegument composed of protein
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The nucleocapsid responsible for the packaging and transport of the genome has become an important target for the development of new herpes virus drugs
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The packaging process of the herpes virus genome is regulated by the genomic pressure inside the nucleocapsid, and the unit length of the genome is packaged through a mechanism called "head-full"
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Portal is not only used as a channel for the entry and exit of the viral genome, but also as a pressure sensor for its internal pressure
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The genome of HCMV (235 kb) is the largest among known human viruses, and its nucleocapsid size is similar to that of other herpes viruses, although there have been multiple α- (herpes simplex virus, HSV) and The in-situ structure of the γ-subfamily (Kaposi's sarcoma-associated virus, KSHV and Epstein-Bar virus, EBV) herpes virus portal has been resolved, but how does the herpes virus portal perceive these different "head-full" signals and how the nucleocapsid Scientific issues such as precise regulation of the genome transfer process through pressure changes have not yet been elucidated
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On July 28, 2021, Nature Communications published online a long research article titled Structural Basis for Genome Packaging, Retention, and Ejection in Human Cytomegalovirus, completed by the team of Researcher Yu Xuekui of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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This study uses cryo-electron microscopy to analyze the in situ structure of the first beta subfamily herpes virus—HCMV's high-resolution portal and capsid vertex-specific components (CVSC), in order to understand herpes virus genome packaging, The molecular mechanism of "pressure sensing and regulation" in the process of stabilization and release provides new ideas
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 In this study, the researchers optimized the HCMV virus culture program to prepare high-quality HCMV samples with a complete envelope and used cryo-electron microscopy to analyze the high-resolution in situ structure of the HCMV nucleocapsid portal and CVSC
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Different from the 5 times (C5)-12 times (C12) double symmetrical mismatch structural features of other herpes virus portals that have been reported, the in-situ structure of the HCMV nucleocapsid portal presents a triple symmetrical mismatch of C5-C6-C12 , Respectively: C5 10-helix anchor domain, C6 portal turret domain and C12 main body domain
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Among them, 10-helix anchor was first discovered in herpes virus, and it interacted with a piece of DNA (pDNA) closely surrounding the portal
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The pDNA is structurally conserved in different herpes viruses.
Researchers believe that its function is to compress the portal during the genome packaging process, and at the same time, the portal also moves outward under the push of internal pressure
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When the portal reaches the outermost position and the tightest conformation, it triggers the "head-full" signal
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Left, HCMV nucleocapsid cryo-EM structure; middle, HCMV portal apex cryo-EM structure; right, HCMV portal in-situ structure model researchers further proposed that HCMV's unique 10-helix anchor functions as a “damper” to delay the nucleus by acting on pDNA The capsid reaches the "head-full" state, thereby realizing the packaging of the super-large genome; secondly, the portal turret with 6-fold symmetry passes through a group of helix structures and the adjacent N-terminal helix structure of the main capsid protein (N-latch) Interaction occurs, providing important support for stabilizing the large genome inside the nucleocapsid; in addition, the researchers found that after the virus envelope ruptures, the nucleocapsid will undergo global displacement and local conformational changes at the apex of the portal, suggesting that the virus invades cells through envelope fusion In, portal can make timely feedback after sensing internal and external pressure changes to ensure the stable and correct release of its internal genome
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Researchers found in previous studies that the number of CVSCs acting on the apex of the capsid is different in different herpes viruses, and is inversely related to the size of the viral genome.
Therefore, they proposed a new mechanism of “stress regulation” assisted by CVSC.
Realize the transfer of viral genome
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This research provides further support for this argument
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The researchers found that the amount of CVSC binding of HCMV was significantly lower than that of HSV-1, KSHV and EBV.
In contrast, HCMV packs the largest genome
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In summary, the research team described the structural conservation and adaptive molecular characteristics of the HCMV nucleocapsid portal, and further explored the new functions of CVSC in viral genome transport, combined with the conformation of the nucleocapsid before and after the viral envelope fusion Changes, systematically elaborated the molecular mechanism of herpes virus to achieve precise regulation of several key steps of viral genome packaging, stabilization, and release
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Associate researcher Li Zhihai of Yu Xuekui's research group at Shanghai Institute of Medicine, master student Pang Jingjing and engineer Dong Lili are the co-first authors of this paper, and researcher Yu Xuekui is the corresponding author of this paper
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This work was supported by the cryo-electron microscopy research center of Shanghai Institute of Medicine
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The project was funded by the National Natural Science Foundation of China, the Shanghai Natural Science Foundation and the Shanghai Yangfan Project
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