Herpes Simplex Virus Requires VP11/12 To Induce Phosphorylation of the Activation Loop Tyrosine (Y394) of the Src Family Kinase Lck in T Lymphocytes

Wagner, Melany J.; Smiley, James R.

doi:10.1128/jvi.01364-09

Cited by 21 publications

(38 citation statements)

References 69 publications

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“…Cell extracts were prepared at 4°C by a 20-min incubation in lysis buffer (1% Nonidet, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EGTA, 10 mM NaF, 10 mM ␤-glycerol phosphate, 1 mM Na 3 VO 4 , 50 mM Tris-HCl [pH 7.4]) supplemented with a complete protease inhibitor cocktail (Roche). Western blotting was performed as described previously (64).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Cell extracts were prepared as described for Western blotting. Immunoprecipitation was performed at 4°C as previously described (64).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…VP11/12, one of the most abundant proteins in the HSV-1 tegument, lacks a well-established function during infection; however, studies from our laboratory suggest that it serves as a substrate and an activator of the lymphocyte-specific Lck tyrosine kinase (64,72). Originally identified as two proteins, VP11 and VP12, based on its mobility relative to that of other virion proteins in a denaturing SDS-polyacrylamide gel (at ca.…”

mentioning

confidence: 99%

“…Our previous studies raised the possibility that VP11/12 modulates one or more cellular signaling pathways (64,72). VP11/12 is highly tyrosine phosphorylated in lymphocytes, and in Jurkat T cells, tyrosine phosphorylation is largely dependent on the lymphocyte-specific Src family kinase (SFK) Lck (72).…”

mentioning

confidence: 99%

“…VP11/12 is highly tyrosine phosphorylated in lymphocytes, and in Jurkat T cells, tyrosine phosphorylation is largely dependent on the lymphocyte-specific Src family kinase (SFK) Lck (72). Lck is activated during HSV-1 infection of T cells, and VP11/12 is required for this effect; moreover, VP11/12 interacts with Lck or Lck signaling complexes (64). These data suggest that VP11/12 activates Lck to induce its own tyrosine phosphorylation, perhaps thereby inducing or modifying downstream signaling events.…”

mentioning

confidence: 99%

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Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner

Smiley

2011

J Virol

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We previously showed that the herpes simplex virus 1 (HSV-1) tegument protein VP11/12 activates the lymphocyte-specific Src family kinase (SFK) Lck and is tyrosine phosphorylated in an Lck-dependent manner during T cell infection. We now extend these findings to show that ectopic expression of Lck induces robust tyrosine phosphorylation of VP11/12 in Vero cells, strongly suggesting that VP11/12 participates in an Lckmediated signaling pathway as a substrate of Lck or a kinase activated by Lck. We sought to elucidate signaling events downstream of VP11/12-SFK interactions. SFKs lie upstream of the canonical phosphoinositide 3-kinase (PI3K)-Akt pathway in signaling emanating from immune receptors, growth factor receptors, and polyomavirus middle T antigen. Here, we show that VP11/12 is required for virus-induced activation of PI3K-Akt signaling in HSV-infected Jurkat T cells and primary fibroblasts. VP11/12 interacts with PI3K or PI3K signaling complexes during infection, suggesting that VP11/12 activates PI3K directly. SFK activity is required for tyrosine phosphorylation of VP11/12, VP11/12-PI3K interactions, and Akt activation in infected fibroblasts, suggesting that SFK-dependent phosphorylation of VP11/12 is required for interactions with downstream signaling effectors. Akt controls many biological functions, including cell survival, cell motility, and translation, but it is currently unclear which Akt targets are modulated by VP11/12 during infection. Although the Akt target mTORC1 is activated during HSV-1 infection, VP11/12 is not required for this effect, implying that one or more additional viral proteins regulate this pathway. Further studies are therefore required to determine which Akt targets and associated biological functions are uniquely modulated by VP11/12.

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Section: Cells and Virusesmentioning

confidence: 99%

“…Cell extracts were prepared as described for Western blotting. Immunoprecipitation was performed at 4°C as previously described (64).…”

Section: Cells and Virusesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner

Smiley

2011

J Virol

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Comprehensive analysis of liquid–liquid phase separation propensities of HSV‐1 proteins and their interaction with host factors

Subedi,

Nag,

Shukla

et al. 2023

J of Cellular Biochemistry

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In recent years, it has been shown that the liquid–liquid phase separation (LLPS) of virus proteins plays a crucial role in their life cycle. It promotes the formation of viral replication organelles, concentrating viral components for efficient replication and facilitates the assembly of viral particles. LLPS has emerged as a crucial process in the replication and assembly of herpes simplex virus‐1 (HSV‐1). Recent studies have identified several HSV‐1 proteins involved in LLPS, including the myristylated tegument protein UL11 and infected cell protein 4; however, a complete proteome‐level understanding of the LLPS‐prone HSV‐1 proteins is not available. We provide a comprehensive analysis of the HSV‐1 proteome and explore the potential of its proteins to undergo LLPS. By integrating sequence analysis, prediction algorithms and an array of tools and servers, we identified 10 HSV‐1 proteins that exhibit high LLPS potential. By analysing the amino acid sequences of the LLPS‐prone proteins, we identified specific sequence motifs and enriched amino acid residues commonly found in LLPS‐prone regions. Our findings reveal a diverse range of LLPS‐prone proteins within the HSV‐1, which are involved in critical viral processes such as replication, transcriptional regulation and assembly of viral particles. This suggests that LLPS might play a crucial role in facilitating the formation of specialized viral replication compartments and the assembly of HSV‐1 virion. The identification of LLPS‐prone proteins in HSV‐1 opens up new avenues for understanding the molecular mechanisms underlying viral pathogenesis. Our work provides valuable insights into the LLPS landscape of HSV‐1, highlighting potential targets for further experimental validation and enhancing our understanding of viral replication and pathogenesis.

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Identification of potential targets of chrysin in treating HSV-1 infection: a network pharmacology study

Liu,

Zheng,

Zhou

et al. 2024

GENOME INSTAB. DIS.

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Herpes Simplex Virus Requires VP11/12 To Induce Phosphorylation of the Activation Loop Tyrosine (Y394) of the Src Family Kinase Lck in T Lymphocytes

Cited by 21 publications

References 69 publications

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Comprehensive analysis of liquid–liquid phase separation propensities of HSV‐1 proteins and their interaction with host factors

Identification of potential targets of chrysin in treating HSV-1 infection: a network pharmacology study

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