Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1.

Proceedings of the National Academy of Sciences of the United States of America
Mariko AoyagiThomas Shenk

Abstract

4EBP1 is phosphorylated by the mTORC1 kinase. When mTORC1 activity is inhibited, hypophosphorylated 4EBP1 binds and sequesters eIF4E, a component of the mRNA cap-binding complex, and blocks translation. As a consequence, mTORC1 activity is needed to maintain active translation. The human cytomegalovirus pUL38 protein preserves mTORC1 activity, keeping most of the E4BP1 in the infected cell in a hyperphosphorylated, inactive state. Here we report that a second viral protein, pUL69, also antagonizes the activity of 4EBP1, but by a separate mechanism. pUL69 interacts directly with eIF4A1, an element of the cap-binding complex, and the poly(A)-binding protein, which binds to the complex. When pUL69 accumulates during infection with wild-type virus, 4EBP1 is excluded from the complex. However, 4EBP1 is present in the cap-binding complex after infection with a pUL69-deficient virus, coincident with reduced accumulation of several late virus-coded proteins. We propose that pUL69 supports translation in human cytomegalovirus-infected cells by excluding hypophosphorylated 4EBP1 from the cap-binding complex.

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Citations

Mar 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Caleb McKinneyIan Mohr
Dec 16, 2011·Journal of Virology·Daniel CygnarWade A Bresnahan
Jun 19, 2012·Virus Research·Fernando Valiente-EcheverríaAndrew J Mouland
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Aug 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jaewon SongKwangseog Ahn
Dec 2, 2010·Biochemical Society Transactions·Derek Walsh
Jan 11, 2020·Frontiers in Immunology·Caroline L AshleyBarry Slobedman
Feb 24, 2019·Virus Genes·Hilda MonteroClara L Sampieri
Aug 9, 2020·Frontiers in Microbiology·Yu-Qing Wang, Xiang-Yu Zhao
May 4, 2021·Frontiers in Oncology·Sandy Haidar AhmadGeorges Herbein

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