Herpes Simplex Virus ICP27 Is Required for Virus-Induced Stabilization of the ARE-Containing IEX-1 mRNA Encoded by the Human IER3 Gene

Abstract

Herpes simplex virus (HSV) stifles cellular gene expression during productive infection of permissive cells, thereby diminishing host responses to infection. Host shutoff is achieved largely through the complementary actions of two viral proteins, ICP27 and virion host shutoff (vhs), that inhibit cellular mRNA biogenesis and trigger global mRNA decay, respectively. Although most cellular mRNAs are thus depleted, some instead increase in abundance after infection; perhaps surprisingly, some of these contain AU-rich instability elements (AREs) in their 3-untranslated regions. ARE-containing mRNAs normally undergo rapid decay; however, their stability can increase in response to signals such as cytokines and virus infection that activate the p38/MK2 mitogen-activated protein kinase (MAPK) pathway. We and others have shown that HSV infection stabilizes the ARE mRNA encoding the stress-inducible IEX-1 mRNA, and a previous report from another laboratory has suggested vhs is responsible for this effect. However, we now report that ICP27 is essential for IEX-1 mRNA stabilization whereas vhs plays little if any role. A recent report has documented that ICP27 activates the p38 MAPK pathway, and we detected a strong correlation between this activity and stabilization of IEX-1 mRNA by using a panel of HSV type 1 (HSV-1) isolates bearing an array of previously characterized ICP27 mutations. Furthermore, IEX-1 mRNA stabilization was abrogated by the p38 inhibitor SB203580. Taken together, these data indicate that the HSV-1 immediate-early protein ICP27 alters turnover of the ARE-containing message IEX-1 by activating p38. As many ARE mRNAs encode proinflammatory cytokines or other immediate-early response proteins, some of which may limit viral replication, it will be of great interest to determine if ICP27 mediates stabilization of many or all ARE-containing mRNAs.Host protein synthesis is rapidly shut off during productive infection with herpes simplex virus type 1 (HSV-1), thereby tempering host responses to infection and allowing viral mRNAs to dominate the host translational apparatus (69). Host shutoff is achieved largely through the complementary actions of ICP27 and the virion host shutoff (vhs) protein, which inhibit host mRNA biogenesis and trigger accelerated mRNA decay, respectively (26,27,41,64,75).The immediate-early ICP27 protein is an essential multifunctional regulator of viral and cellular gene expression, possessing both activating and repressive functions (47, 76). It binds RNA (50) and shuttles between the nucleus and the cytoplasm (46,49,59,70,77), properties that likely contribute to its ability to activate expression of certain viral genes. In this context, it has been proposed to aid in the transport of intronless viral messages to the cytoplasm via interactions with the cellular mRNA transport factors Aly/Ref (7, 39) and/or TAP1 (8); however, the functional significance of the interaction with Aly/Ref remains uncertain, as a mutation that eliminates the interaction interface has a relatively minor ef...

Herpes Simplex Virus Type 1 ICP27 Induces p38 Mitogen-Activated Protein Kinase Signaling and Apoptosis in HeLa Cells

“…Previous reports using viral deletion mutants have shown that ICP27 expression is required during HSV-1 infection for p38 activation (12,23,24). The study presented in this paper, however, is the first to show that ICP27 expression alone is sufficient for the activation of p38 signaling.…”

“…The timing of the activation pointed toward an IE gene product as being responsible for initial induction since IE proteins are present at high levels at 3 hpi. Consistent with this, studies showed that ICP27 is required in the context of viral infection for activation of the SAPK pathways (12,23,24). The N-terminal end of the ICP27 protein, which plays a functional role in nuclear export, is required for SAPK activation (12,23,33).…”

“…Consistent with this, studies showed that ICP27 is required in the context of viral infection for activation of the SAPK pathways (12,23,24). The N-terminal end of the ICP27 protein, which plays a functional role in nuclear export, is required for SAPK activation (12,23,33). Additionally, it was shown that ICP27-mediated JNK signaling leads to the activation of NF-B during viral infection (24).…”

“…Furthermore, ICP27 inhibits normal cellular gene expression by inhibiting mRNA splicing as well as the transcription of some host genes (21,22,46,51). ICP27 expression can also lead to increased expression of some cellular mRNAs due to stabilization of transcripts containing AU-rich elements (7,12).…”

The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition

“…Besides an induced gene transcription mediated by the p44/p42 MAPK and AP1 pathway, stabilization of IEX-1 mRNA by G17 may also account for the elevated IEX-1 expression. IEX-1 mRNA contains a half-life time-regulating A-rich element (ARE) within its 3 0 -UTR, and this element is under the control of the p38 MAPK pathway (Corcoran et al, 2006), which is induced in Colo320wt cells by G17 as well (Yu et al, 2005). Of note, G17 similarly induces IEX-1 expression in the colorectal cancer cell line LoVo (Supplementary material 2) also expressing the CCK-2 receptor and exhibiting an apoptotic response to G17 treatment .…”