scholarly journals Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt

2020 ◽  
Vol 94 (16) ◽  
Author(s):  
Jamil Mahmud ◽  
Michael J. Miller ◽  
Aaron M. Altman ◽  
Gary C. Chan
Keyword(s):  
Growth Factor ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Growth Factor Receptor ◽  
Direct Consequence ◽  
Akt Signaling ◽  
Sh2 Domain ◽  
Receptor Signaling ◽  
Integrin Β1 ◽  
Hcmv Disease

ABSTRACT Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality among immunocompromised and immunonaive individuals. HCMV-induced signaling initiated during viral entry stimulates a rapid noncanonical activation of Akt to drive the differentiation of short-lived monocytes into long-lived macrophages, which is essential for viral dissemination and persistence. We found that HCMV glycoproteins gB and gH directly bind and activate cellular epidermal growth factor receptor (EGFR) and integrin β1, respectively, to reshape canonical Akt signaling within monocytes. The remodeling of the Akt signaling network was due to the recruitment of nontraditional Akt activators to either the gB- or gH-generated receptor signaling complexes. Phosphoinositide 3-kinase (PI3K) comprised of the p110β catalytic subunit was recruited to the gB/EGFR complex despite p110δ being the primary PI3K isoform found within monocytes. Concomitantly, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) was recruited to the gH/integrin β1 complex, which is critical to aberrant Akt activation, as SHIP1 diverts PI3K signaling toward a noncanonical pathway. Although integrin β1 was required for SHIP1 recruitment, gB-activated EGFR mediated SHIP1 activation, underscoring the importance of the interplay between gB- and gH-mediated signaling to the unique activation of Akt during HCMV infection. Indeed, SHIP1 activation mediated the increased expression of Mcl-1 and HSP27, two Akt-dependent antiapoptotic proteins specifically upregulated during HCMV infection but not during growth factor treatment. Overall, our data indicate that HCMV glycoproteins gB and gH work in concert to initiate an HCMV-specific signalosome responsible for the atypical activation of Akt required for infected monocyte survival and ultimately viral persistence. IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic throughout the world regardless of socioeconomic conditions and geographic locations with a seroprevalence reaching up to 100% in some developing countries. Although asymptomatic in healthy individuals, HCMV can cause severe multiorgan disease in immunocompromised or immunonaive patients. HCMV disease is a direct consequence of monocyte-mediated systematic spread of the virus following infection. Because monocytes are short-lived cells, HCMV must subvert the natural short life-span of these blood cells by inducing a distinct activation of Akt, a serine/theonine protein kinase. In this work, we demonstrate that HCMV glycoproteins gB and gH work in tandem to reroute classical host cellular receptor signaling to aberrantly activate Akt and drive survival of infected monocytes. Deciphering how HCMV modulates the cellular pathway to induce monocyte survival is important to develop a new class of anti-HCMV drugs that could target and prevent spread of the virus by eliminating infected monocytes.

scholarly journals Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes

2016 ◽  
Vol 90 (14) ◽  
pp. 6443-6452 ◽  
Author(s):  
Olesea Cojohari ◽  
Megan A. Peppenelli ◽  
Gary C. Chan
Keyword(s):  
Growth Factor ◽  
Life Span ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Akt Signaling ◽  
Sh2 Domain ◽  
Signaling Network ◽  
Morbidity And Mortality ◽  
Blood Monocytes ◽  
Viral Dissemination

ABSTRACTHuman cytomegalovirus (HCMV) is a pervasive herpesvirus responsible for significant morbidity and mortality among immunodeficient/naive hosts. Following a primary HCMV infection, circulating blood monocytes mediate the systemic spread of the virus. Extending the short 48-h life span of monocytes is critical to the viral dissemination process, as these blood-borne cells are nonpermissive for virus replication until they are fully differentiated into macrophages. Here, we show that HCMV glycoprotein gB binding to cellular epidermal growth factor receptor (EGFR) during HCMV entry initiated a rapid (within 15 min) activation of the apoptosis suppressor Akt, which was maintained through 72 h. The virus-induced activation of Akt was more robust than that with the normal myeloid growth factor macrophage colony-stimulating factor (M-CSF) and was essential for infected monocytes to bypass the 48-h viability checkpoint. Activation of phosphoinositide 3-kinase (PI3K) following EGFR engagement by HCMV mediated the phosphorylation of Akt. Moreover, HCMV entry drove a switch away from the PI3K p110δ isoform, which was required for the viability of uninfected monocytes, to the p110β isoform in order to facilitate the Akt-dependent prosurvival state within infected cells. Simultaneously, in contrast to M-CSF, HCMV promoted a rapid increase in SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) expression, leading to signaling through a noncanonical Akt activation pathway. To ensure maximum Akt activity, HCMV also induced an early phosphorylation-dependent inactivation of the negative regulator phosphatase and tensin homolog. Overall, our data indicate that HCMV hijacks the upstream Akt signaling network to induce a nontraditional activation of Akt and subsequently a prosurvival decision at the 48-h cell fate checkpoint, a vital step for HCMV's dissemination and persistence strategy.IMPORTANCEHCMV is found throughout the world with a prevalence of 55 to 100% within the human population. HCMV infection is generally asymptomatic in immunocompetent or naive individuals but is a significant cause of morbidity and mortality among the immunocompromised. Widespread organ inflammation is associated with symptomatic infections, which is a direct consequence of the viral dissemination strategy. Inflammatory peripheral blood monocytes facilitate the spread of HCMV. However, HCMV must subvert the naturally short life span of monocytes. In this work, we demonstrate that HCMV induces the activation of Akt, an antiapoptotic protein, in a manner distinct from that of normal myeloid growth factors. Moreover, we decipher how HCMV dysregulates the upstream Akt signaling network during viral entry to promote an Akt-dependent prosurvival state following infection. Delineation of the virus-specific mechanisms that regulate cellular prosurvival pathways in order to drive the survival of HCMV-infected monocytes is important to identifying new anti-HCMV therapeutic targets.

scholarly journals Human Cytomegalovirus UL135 Interacts with Host Adaptor Proteins To Regulate Epidermal Growth Factor Receptor and Reactivation from Latency

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Michael A. Rak ◽  
Jason Buehler ◽  
Sebastian Zeltzer ◽  
Justin Reitsma ◽  
Belen Molina ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Growth Factor Receptor ◽  
Adaptor Proteins ◽  
Recombinant Viruses ◽  
Hcmv Disease ◽  
Epidermal Growth

ABSTRACTHuman cytomegalovirus, HCMV, is a betaherpesvirus that establishes a lifelong latent infection in its host that is marked by recurrent episodes of reactivation. The molecular mechanisms by which the virus and host regulate entry into and exit from latency remain poorly understood. We have previously reported thatUL135is critical for reactivation, functioning in part by overcoming suppressive effects of the latency determinantUL138. We have demonstrated a role forUL135in diminishing cell surface levels and targeting epidermal growth factor receptor (EGFR) for turnover. The attenuation of EGFR signaling promotes HCMV reactivation in combination with cellular differentiation. In this study, we sought to define the mechanisms by whichUL135functions in regulating EGFR turnover and viral reactivation. Screens to identify proteins interacting with pUL135 identified two host adaptor proteins, CIN85 and Abi-1, with overlapping activities in regulating EGFR levels in the cell. We mapped the amino acids in pUL135 necessary for interaction with Abi-1 and CIN85 and generated recombinant viruses expressing variants of pUL135 that do not interact with CIN85 or Abi-1. These recombinant viruses replicate in fibroblasts but are defective for reactivation in an experimental model for latency using primary CD34+hematopoietic progenitor cells (HPCs). TheseUL135variants have altered trafficking of EGFR and are defective in targeting EGFR for turnover. These studies demonstrate a requirement for pUL135 interactions with Abi-1 and CIN85 for regulation of EGFR and mechanistically link the regulation of EGFR to reactivation.IMPORTANCEHuman cytomegalovirus (HCMV) establishes a lifelong latent infection in the human host. While the infection is typically asymptomatic in healthy individuals, HCMV infection poses life-threatening disease risk in immunocompromised individuals and is the leading cause of birth defects. Understanding how HCMV controls the lifelong latent infection and reactivation of replication from latency is critical to developing strategies to control HCMV disease. Here, we identify the host factors targeted by a viral protein that is required for reactivation. We define the importance of this virus-host interaction in reactivation from latency, providing new insights into the molecular underpinnings of HCMV latency and reactivation.

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