Human Cytomegalovirus Protein UL38 Inhibits Host Cell Stress Responses by Antagonizing the Tuberous Sclerosis Protein Complex

Moorman, Nathaniel J.; Cristea, Ileana M.; Terhune, Scott S.; Rout, Michael P.; Chait, Brian T.; Shenk, Thomas

doi:10.1016/j.chom.2008.03.002

Cited by 178 publications

(253 citation statements)

References 60 publications

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“…We have previously reported that HCMV-coded pUL38 maintains activity of mTORC1 within infected cells, so that the majority of 4EBP1 is hyperphosphorylated (28). However, a minor portion of 4EBP1 remains hypophosphorylated in infected cells (28), and this is presumably the 4EBP1 that is antagonized by pUL69. It is well established that 4EBP1 is not degraded after HCMV infection (24,29), so it is likely that pUL69 blocks access of 4EBP1 to the m 7 G-cap complex through its contacts with eIF4A1 and PABPC1.…”

Section: Discussionmentioning

confidence: 99%

“…Hypophosphorylated 4EBP1 binds to eIF4E and blocks assembly of the cap-binding complex; mTORC1 phosphorylates 4EBP1, and the hyperphosphorylated factor doesn't bind to eIF4E or inhibit translation (18). We have previously reported that HCMV-coded pUL38 maintains activity of mTORC1 within infected cells, so that the majority of 4EBP1 is hyperphosphorylated (28). However, a minor portion of 4EBP1 remains hypophosphorylated in infected cells (28), and this is presumably the 4EBP1 that is antagonized by pUL69.…”

Section: Discussionmentioning

confidence: 99%

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

Aoyagi

Gaspar

Shenk

2010

Proc. Natl. Acad. Sci. U.S.A.

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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.translational control | two-hybrid screen | eukaryotic initiation factor 4A

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Aoyagi

Gaspar

Shenk

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…How is active AMPK decoupled from some of its downstream substrates? The HCMV pUL38 protein binds to TSC2 and prevents TSC1/2 from responding to AMPK phosphorylation (39). Although ACC is induced and required for HCMV replication (34), the mechanism by which it is protected from inactivation by AMPK after infection is unknown.…”

Section: Discussionmentioning

confidence: 99%

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Terry¹,

Vastag

Rabinowitz

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus (HCMV) modulates numerous cellular signaling pathways. Alterations in signaling are evident from the broad changes in cellular phosphorylation that occur during HCMV infection and from the altered activity of multiple kinases. Here we report a comprehensive RNAi screen, which predicts that 106 cellular kinases influence growth of the virus, most of which were not previously linked to HCMV replication. Multiple elements of the AMP-activated protein kinase (AMPK) pathway scored in the screen. As a regulator of carbon and nucleotide metabolism, AMPK is poised to activate many of the metabolic pathways induced by HCMV infection. An AMPK inhibitor, compound C, blocked a substantial portion of HCMV-induced metabolic changes, inhibited the accumulation of all HCMV proteins tested, and markedly reduced the production of infectious progeny. We propose that HCMV requires AMPK or related activity for viral replication and reprogramming of cellular metabolism.herpesvirus | siRNA V iruses are dependent on host cell signaling pathways for replication and spread. Infection with the prevalent β-herpes virus human cytomegalovirus (HCMV) induces increased levels of protein phosphorylation and markedly alters host cell signal transduction pathways (1). A portion of the phosphorylation changes induced by HCMV infection are attributed to the Ser/ Thr kinase encoded by the viral genome, pUL97 (2), and others may derive from cellular kinase(s) packaged into virions (3) or from cellular kinases known to be activated by HCMV (4).Here we sought to more completely delineate the effects of HCMV infection on kinase signaling by performing an siRNA screen of the entire cellular kinome. The screen identified 106 kinases predicted to influence the production of virus. The hits included the 5′-AMP-activated protein kinase (AMPK), a sensor of cellular energy homeostasis. AMPK is composed of three subunits: a catalytic subunit, AMPKα, and two regulatory subunits, AMPKβ and AMPKγ. Activation of the kinase requires cooperative AMP binding to AMPKγ, which occurs stochastically with shifts in the AMP:ATP ratio, and phosphorylation of AMPKα at Thr172 (5, 6). At least three different kinases are reported to phosphorylate Thr172 of AMPKα: Ca 2+ /calmodulindependent kinase kinase (CaMKK), TGF-β-activated kinase 1 (TAK1), and liver kinase B1 (LKB1) (7). Activated AMPK phosphorylates a number of substrates to effect changes in central carbon metabolism, lipid metabolism, physiological homeostasis, cell growth, apoptosis, and gene expression (5).HCMV induces glycolysis (8-10) and also causes increased levels of the glucose transporter GLUT4 at the plasma membrane increasing glucose uptake (11).AMPK controls GLUT4 relocalization to the plasma membrane (5), and this regulation likely links the kinase to altered metabolism in HCMV-infected cells. However, previous work indicates that pharmacological activation of AMPK during the early phase of HCMV infection can be deleterious to viral replication (12), yet CaMKK activity is required for ...

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“…In addition, HCMV infection activates signaling pathways that stimulate eIF4F complex formation. For example, HCMV activates the mTOR kinase (13)(14)(15)(16). Active mTOR facilitates eIF4F complex formation by phosphorylating and antagonizing the translation repressor 4EBP-1, which prevents the formation of eIF4F on the mRNA cap (17,18).…”

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confidence: 99%

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

Lenarcic

Ziehr

Leon

et al. 2014

J Virol

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The host eIF4F translation initiation complex plays a critical role the translation of capped mRNAs. Although human cytomegalovirus (HCMV) infection increases the abundance and activity of the host eIF4F complex, the requirement for eIF4F components in HCMV replication and mRNA translation has not been directly tested. In this study, we found that decreasing the abundance or activity of eIF4F from the start of infection inhibits HCMV replication. However, as infection progresses, viral mRNA translation and replication becomes increasingly resistant to eIF4F inhibition. During the late stage of infection the association of representative immediate-early, early, and late mRNAs with polysomes was not affected by eIF4F disruption. In contrast, eIF4F inhibition decreased the translation of representative host eIF4F-dependent mRNAs during the late stage of infection. A global analysis of the translation efficiency of HCMV mRNAs during the late stage of infection found that eIF4F disruption had a minimal impact on the association of HCMV mRNAs with polysomes but significantly diminished the translation efficiency of eIF4F-dependent host transcripts. Together, our data show that the translation of host eIF4F-dependent mRNAs remains dependent on eIF4F activity during HCMV infection. However, during the late stage of infection the translation efficiency of viral mRNAs does not correlate with the abundance or activity of the host eIF4F complex.

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Human Cytomegalovirus Protein UL38 Inhibits Host Cell Stress Responses by Antagonizing the Tuberous Sclerosis Protein Complex

Cited by 178 publications

References 60 publications

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

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

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

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