Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38

Abstract

We previously reported that herpes simplex virus type 1 (HSV-1) can activate the stress-activated protein kinases (SAPKs) p38 and JNK. In the present study, we undertook a comprehensive and comparative analysis of the requirements for viral protein synthesis in the activation of JNK and p38. Infection with the UL36 mutant tsB7 or with UV-irradiated virus indicated that both JNK The stress-activated protein kinases (SAPKs) p38 and JNK are part of a larger family of serine/threonine terminal kinases termed mitogen-activated protein kinases (MAPK), which includes ERK1 and -2. SAPK pathways are normally activated by UV irradiation, anoxia, and engagement of proinflammatory cytokines or Fas ligand by their cognate receptors. Following ligand binding to a cognate receptor, signaling is initiated through receptor-associated kinases to a MAPKKK (MAPK kinase kinase). MAPKKKs capable of initiating the p38 or JNK pathway include MEKK1, -2, -3, and -4, ASK-1, TAK-1, and TAO. These in turn activate dual-specificity MAPK kinase kinases (MAPKKs) MKK3/6 and MKK4/7, which directly bind and phosphorylate p38 and JNK, respectively, on both tyrosine and threonine, resulting in their activation (for a review, see reference 78).All three subfamilies of human herpesviruses activate one or more of the MAPKs during infection. The betaherpesvirus cytomegalovirus activates both p38 and ERK by a mechanism dependent on viral gene expression (14,39,76) and the upstream kinases MKK3/6 and MKK1/2, respectively, (39, 40). ERK activates the early gene UL112-113 promoter (76) and phosphorylates immediate-early 86 and 72 proteins to alter their transactivation activity (40), while p38 phosphorylates retinoblastoma protein and HSP27 (39). ERK and p38 activation are required for cytomegalovirus DNA replication (16). The gammaherpesvirus Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor activates ERK and p38, causing increased vascular endothelial growth factor expression via phosphorylation of hypoxia-inducible factor 1␣ (86). The gammaherpesvirus Epstein-Barr virus activates p38 and JNK (1, 21). The immediate-early proteins BZLF1 and BRLF1 induce increased phosphorylation of p38 and JNK and activation of the ATF-2 transcription factor (1). BZLF1 expression during BRLF1-driven virus reactivation requires p38 activity (1). Among the alphaherpesviruses, HSV-2 has been reported to activate ERK through ICP10-PK binding to RAS-GAP, leading to further expression of ICP10 and prevention of apoptosis (68).Two previous reports documented the activation of the p38 and JNK (SAPK) pathways by HSV-1. Increased JNK and p38 kinase activity was observed as early as 3 hours postinfection and remained active throughout the course of infection (56,97). SAPKs were activated downstream of Ras, as infection with a dominant-negative form of Ras did not affect activation of the transcription factors ATF-2 and c-Jun, downstream targets of p38 and JNK, respectively (56). Furthermore, activation was specific for SAPKs, as ERK was not activated during infect...

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

“…As expected, HTO-H cells infected with d27-1 virus show little if any JNK phosphorylation (data not shown), consistent with prior results that indicated that ICP27 is required for JNK activation (23,24). In contrast, high levels of nuclear phosphorylated JNK were seen in both KOS and d27-1-infected TE51 cells ( Fig.…”

“…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).…”

“…The observation that ICP27 expression alone activates p38 signaling but is apparently insufficient to activate JNK signaling is interesting in light of the results of Hargett et al (23,24), who showed that ICP27 is required for JNK activation during infection. However, it is possible that the JNK immunoblotting assay is not sensitive enough to detect low levels of JNK phosphorylation in a subset of the total cell population.…”

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

“…Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”