Cyclin E2‐<scp>CDK</scp>2 mediates <scp>SAMHD</scp>1 phosphorylation to abrogate its restriction of <scp>HBV</scp> replication in hepatoma cells

Hu, Jie; Qiao, Miao; Chen, Yanmeng; Tang, Hua; Zhang, Wenlu; Tang, Dan; Pi, Sidie; Dai, Juan; Tang, Ni; Huang, Aiping; Hu, Yuan

doi:10.1002/1873-3468.13105

Cited by 26 publications

(26 citation statements)

References 34 publications

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“…Moreover, inhibitors of CDKs have been shown to modulate HBV infection with different outcomes. On the one hand, KO or inhibition of CDK2 enhances HBV replication by phosphorylation and deactivation of the host restriction factor SAMHD1 41 . On the other hand, the CDK9 inhibitor FIT039 prevents replication of HBV and other DNA viruses and is under consideration as an antiviral candidate against HBV 42,43 .…”

Section: Discussionmentioning

confidence: 99%

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

et al. 2020

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Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.

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Section: Discussionmentioning

confidence: 99%

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

et al. 2020

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“…Several studies have shown that phosphorylation at T592 negatively regulates SAMHD1 restriction activity [34][35][36][37][38]40,[43][44][45][46][47][48]. The crystal structure of the human SAMHD1 tetramer revealed that residue T592 is localized between two small helices within the C-terminal region of SAMHD1, close to the dimer/dimer interface.…”

Section: Samhd1 Is Phosphorylated At T592 In Hcmv-infected Cellsmentioning

confidence: 99%

SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

et al. 2020

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SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.

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“…In addition to viral protein phosphorylation, phosphorylation of the host factors can also influence the process of viral replication. For example, Hu et al (2018) found that the inhibitory effect of SAMHD1 (a restriction factor of HBV) on HBV replication is abrogated when SAMHD1 is phosphorylated by CDK2.…”

Section: The Role Of Phosphorylation In the Regulation Of Hbv Life Cymentioning

confidence: 99%

Post-translational Modification Control of HBV Biological Processes

Yang

2018

Front. Microbiol.

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Hepatitis B virus infection remains a global healthy issue that needs to be urgently solved. Novel strategies for anti-viral therapy are based on exploring the effective diagnostic markers and therapeutic targets of diseases caused by hepatitis B virus (HBV) infection. It is well-established that not only viral proteins themselves but also key factors from the host control the biological processes associated with HBV, including replication, transcription, packaging, and secretion. Protein post-translational modifications (PTMs), such as phosphorylation, acetylation, methylation, and ubiquitination, have been shown to control protein activity, regulate protein stability, promote protein interactions and alter protein subcellular localization, leading to the modulation of crucial signaling pathways and affected cellular processes. This review focuses on the functions and effects of diverse PTMs in regulating important processes in the HBV life cycle. The potential roles of PTMs in the pathogenesis of HBV-associated liver diseases are also discussed.

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Cyclin E2‐CDK2 mediates SAMHD1 phosphorylation to abrogate its restriction of HBV replication in hepatoma cells

Cited by 26 publications

References 34 publications

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

Post-translational Modification Control of HBV Biological Processes

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