Distinct early role of PTEN regulation during HCMV infection of monocytes

• 成果类型: Article
• 署名作者: Chesnokova, Liudmila S.; Mosher, Bailey S.; Fulkerson, Heather L.; Nam, Hyung W.; Shakya, Akhalesh K.; Yurochko, Andrew D.
• 署名单位: Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport; Louisiana State University System; Louisiana State University Health Sciences Center at Shreveport
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10705
• DOI: 10.1073/pnas.2312290121
• 发表日期: 2024-03-19
• 关键词: human cytomegalovirus entry; protein-kinase ck2; epidermal-growth-factor; tumor-suppressor pten; endothelial-cells; temporal regulation; factor receptor; low-ph; phosphorylation; virus

摘要

Human cytomegalovirus (HCMV) infection of monocytes is essential for viral dissemination and persistence. We previously identified that HCMV entry/internalization and subsequent productive infection of this clinically relevant cell type is distinct when compared to other infected cells. We showed that internalization and productive infection required activation of epidermal growth factor receptor (EGFR) and integrin/c-Src, via binding of viral glycoprotein B to EGFR, and the pentamer complex to beta 1/beta 3 integrins. To understand how virus attachment drives entry, we compared infection of monocytes with viruses containing the pentamer vs. those without the pentamer and then used a phosphoproteomic screen to identify potential phosphorylated proteins that influence HCMV entry and trafficking. The screen revealed that the most prominent pentamer- biased phosphorylated protein was the lipid- and protein- phosphatase phosphatase and tensin homolog (PTEN). PTEN knockdown with siRNA or PTEN inhibition with a PTEN inhibitor decreased pentamer- mediated HCMV entry, without affecting trimer- mediated entry. Inhibition of PTEN activity affected lipid metabolism and interfered with the onset of the endocytic processes required for HCMV entry. PTEN inactivation was sufficient to rescue pentamer-null HCMV from lysosomal degradation. We next examined dephosphorylation of a PTEN substrate Rab7, a regulator of endosomal maturation. Inhibition of PTEN activity prevented dephosphorylation of Rab7. Phosphorylated Rab7, in turn, blocked early endosome to late endosome maturation and promoted nuclear localization of the virus and productive infection.