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J Virol. 2009 May;83(10):5181-91. doi: 10.1128/JVI.00090-09. Epub 2009 Mar 11.

Phosphorylation of the U(L)31 protein of herpes simplex virus 1 by the U(S)3-encoded kinase regulates localization of the nuclear envelopment complex and egress of nucleocapsids.

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  • 1Department of Microbiology and Immunology, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA.


Herpes simplex virus 1 nucleocapsids bud through the inner nuclear membrane (INM) into the perinuclear space to obtain a primary viral envelope. This process requires a protein complex at the INM composed of the U(L)31 and U(L)34 gene products. While it is clear that the viral kinase encoded by the U(S)3 gene regulates the localization of pU(L)31/pU(L)34 within the INM, the molecular mechanism by which this is accomplished remains enigmatic. Here, we have determined the following. (i) The N terminus of pU(L)31 is indispensable for the protein's normal function and contains up to six serines that are phosphorylated by the U(S)3 kinase during infection. (ii) Phosphorylation at these six serines was not essential for a productive infection but was required for optimal viral growth kinetics. (iii) In the presence of active U(S)3 kinase, changing the serines to alanine caused the pU(L)31/pU(L)34 complex to aggregate at the nuclear rim and caused some virions to accumulate aberrantly in herniations of the nuclear membrane, much as in cells infected with a U(S)3 kinase-dead mutant. (iv) The replacement of the six serines of pU(L)31 with glutamic acid largely restored the smooth distribution of pU(L)34/pU(L)31 at the nuclear membrane and precluded the accumulation of virions in herniations whether or not U(S)3 kinase was active but also precluded the optimal primary envelopment of nucleocapsids. These observations indicate that the phosphorylation of pU(L)31 by pU(S)3 represents an important regulatory event in the virion egress pathway that can account for much of pU(S)3's role in nuclear egress. The data also suggest that the dynamics of pU(L)31 phosphorylation modulate both the primary envelopment and the subsequent fusion of the nascent virion envelope with the outer nuclear membrane.

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