SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity
| العنوان: | SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity |
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| المؤلفون: | Rossella Paolini, Alessandra Zingoni, Benedetta Pignoloni, Valentina Dell'Oste, Ilaria Nardone, Alessandra Coscia, John Hiscott, Laura Fantuzzi, Fredrik Edfors, Daniela Angela Covino, Simone De Meo, Monsef Benkirane, Angela Santoni, Rosa Molfetta, Lavinia Vittoria Lotti, Cristina Cerboni, Tatyana Sandalova, Santo Landolfo, Simone Vespa, Adnane Achour, Roberta Bona, Matteo Biolatti, Valentina Tassinari |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 16, Iss 9, p e1008855 (2020) |
| بيانات النشر: | Public Library of Science (PLoS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cytomegalovirus Infection, Human cytomegalovirus, Cytoplasm, Viral Diseases, Small interfering RNA, Physiology, viruses, Cytomegalovirus, Virus Replication, Pathology and Laboratory Medicine, Biochemistry, Medical Conditions, cytomegalovirus, SAMHD1, immune evasion, Immune Physiology, Medicine and Health Sciences, Biology (General), Phosphorylation, Post-Translational Modification, 0303 health sciences, Immune System Proteins, biology, Kinase, 030302 biochemistry & molecular biology, Herpesviridae Infections, Cyclin-Dependent Kinases, Cell biology, Nucleic acids, Infectious Diseases, Medical Microbiology, Viral Pathogens, Cytomegalovirus Infections, Viruses, Human Cytomegalovirus, Cellular Structures and Organelles, Pathogens, Research Article, Herpesviruses, QH301-705.5, Immunoblotting, Immunology, Molecular Probe Techniques, Research and Analysis Methods, Antiviral Agents, Microbiology, Antibodies, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, Virology, Genetics, medicine, Humans, Non-coding RNA, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Monomeric GTP-Binding Proteins, 030304 developmental biology, Cyclin-dependent kinase 2, Organisms, Biology and Life Sciences, Proteins, Cell Biology, RC581-607, medicine.disease, Viral Replication, Gene regulation, Viral replication, biology.protein, RNA, Parasitology, Gene expression, Immunologic diseases. Allergy, DNA viruses |
| الوصف: | 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. Author summary Human cytomegalovirus (HCMV) is among the most widespread viruses worldwide, causing severe systemic illness in individuals without a fully competent immune system (e.g., transplanted patients and infants). Therefore, host immune response is crucial to control HCMV replication and dissemination throughout the organism. Some frontline proteins belonging to the innate immune system, known as restriction factors, are already expressed and active even before a pathogen infects a cell and are able to mediate a cell-intrinsic resistance to infections. Among them is SAMHD1, a nuclear deoxynucleotide triphosphate (dNTP) hydrolase that limits the availability of intracellular dNTPs, essential components of growing DNA molecules, including those of replicating viruses. We thus investigated SAMHD1 ability to counteract HCMV infection. We show that SAMHD1 expression was upregulated after infection, but with only a modest effect in limiting viral replication. This was mainly due to HCMV-induced phosphorylation at Threonine-592 (the key residue known to negatively regulate viral restriction), to phosphoT592-SAMHD1 relocalization to the cytoplasm of infected cells, and to its association with viral particles. The unprecedented observation of relocation of phosphoT592-SAMHD1 outside the nucleus may affect SAMHD1 function upon HCMV infection, and thus might represent a novel HCMV-mediated immune evasion strategy that will need further investigations. |
| تدمد: | 1553-7374 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd74128a03bd7aa55863bb6a4e28e5a3Test https://doi.org/10.1371/journal.ppat.1008855Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bd74128a03bd7aa55863bb6a4e28e5a3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 |
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