Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

Zhang, Aiping; Hildreth, Richard L.; Colberg-Poley, Anamaris M.

doi:10.1128/jvi.00145-13

Cited by 39 publications

(39 citation statements)

References 80 publications

(166 reference statements)

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“…MAMs are hubs for lipid synthesis and transfer, signaling, metabolic flow, and apoptosis (71,(74)(75)(76)(77)(78)(79)(80)(81)(82)(83). A precedent for this route is provided by the pUL37x1 protein of human cytomegalovirus, which has been shown to traffic to mitochondria by passing through MAMs (84)(85)(86). Perhaps UL16 utilizes its interaction with gE, which is made in the ER, to gain access to mitochondria via MAMs.…”

Section: Discussionmentioning

confidence: 99%

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Chadha

Sarfo

Zhang

et al. 2017

J Virol

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The UL16 tegument protein of herpes simplex virus 1 (HSV-1) is conserved among all herpesviruses and plays many roles during replication. This protein has an N-terminal domain (NTD) that has been shown to bind to several viral proteins, including UL11, VP22, and glycoprotein E, and these interactions are negatively regulated by a C-terminal domain (CTD). Thus, in pairwise transfections, UL16 binding is enabled only when the CTD is absent or altered. Based on these results, we hypothesized that direct interactions occur between the NTD and the CTD. Here we report that the separated and coexpressed functional domains of UL16 are mutually responsive to each other in transfected cells and form complexes that are stable enough to be captured in coimmunoprecipitation assays. Moreover, we found that the CTD can associate with itself. To our surprise, the CTD was also found to contain a novel and intrinsic ability to localize to specific spots on mitochondria in transfected cells. Subsequent analyses of HSV-infected cells by immunogold electron microscopy and live-cell confocal imaging revealed a population of UL16 that does not merely accumulate on mitochondria but in fact makes dynamic contacts with these organelles in a time-dependent manner. These findings suggest that the domain interactions of UL16 serve to regulate not just the interaction of this tegument protein with its viral binding partners but also its interactions with mitochondria. The purpose of this novel interaction remains to be determined. IMPORTANCEThe HSV-1-encoded tegument protein UL16 is involved in multiple events of the virus replication cycle, ranging from virus assembly to cell-cell spread of the virus, and hence it can serve as an important drug target. Unfortunately, a lack of both structural and functional information limits our understanding of this protein. The discovery of domain interactions within UL16 and the novel ability of UL16 to interact with mitochondria in HSV-infected cells lays a foundational framework for future investigations aimed at deciphering the structure and function of not just UL16 of HSV-1 but also its homologs in other herpesviruses.KEYWORDS domains, HSV-1, herpes simplex virus, mitochondria, tegument, UL16 H erpes simplex virus 1 (HSV-1) contains a 373-amino-acid tegument protein, UL16 (Fig. 1), which is conserved among all families of herpesviruses (1-15). Encoded by the late-expressing 16th open reading frame in the unique long segment of the viral genome, UL16 initially localizes to both the nucleus and the cytoplasm of the infected cell but later accumulates in the cytoplasm (4, 16). There, a population of UL16 is found to be stably associated with an unknown partner on cytoplasmic capsids (16,17), where it plays a role in envelopment by providing bridging functions via its interaction with at least three viral membrane proteins: UL11, glycoprotein E (gE), and VP22 (12, 18-43). Thus, UL16-null mutants produce only 1/10 the number of wild-type virions (1, 12), and

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Section: Discussionmentioning

confidence: 99%

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Chadha

Sarfo

Zhang

et al. 2017

J Virol

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“…vMIA es sintetizado en la membrana del RE, donde permanece anclado a la membrana a través un extremo N-terminal hidrofóbico y transita hacia contactos del RE con la mitocondria denominados membranas asociadas a mitocondria (MAM) 18 . En las regiones MAM, vMIA regula la homeostasis del calcio y combate las respuestas de estrés celular que pueden desembocar en apoptosis 19 . Recientemente, se evidenció que vMIA puede reclutar a Bax hacia las MAM donde es marcada para su degradación proteosomal, ejerciendo de esta manera un mecanismo redundante para bloquear la actividad apoptótica de Bax en la célula infectada 19 .…”

Section: Inhibición De La Apoptosis Por CMVunclassified

“…En las regiones MAM, vMIA regula la homeostasis del calcio y combate las respuestas de estrés celular que pueden desembocar en apoptosis 19 . Recientemente, se evidenció que vMIA puede reclutar a Bax hacia las MAM donde es marcada para su degradación proteosomal, ejerciendo de esta manera un mecanismo redundante para bloquear la actividad apoptótica de Bax en la célula infectada 19 .…”

Section: Inhibición De La Apoptosis Por CMVunclassified

“…El complejo formado recibe el nombre de complejo de señalización inductor de la muerte (DISC) y permite la agregación y autoactivación de procaspasas-8, que a su vez activarán a una caspasa efectora como la caspasa-3 13 . En este proceso pueden intervenir proteínas anti-apoptóticas que son denominadas FLIP (proteínas inhibidoras de FLICE:enzima convertidora de interleucina-1β tipo FADD), y cuya función es la inhibición de la activación de la procaspasa-8 al competir por FADD, ya que estas proteínas también contienen un dominio DED 19 .…”

Section: Inhibición De La Apoptosis Por CMVunclassified

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Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central

González-Sánchez¹,

Silva‐Ramírez²,

Campo³

2016

Rev. chil. infectol.

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“…At the start of lytic infection, human cytomegalovirus (HCMV), a ubiquitous herpesvirus that causes significant morbidity and mortality in individuals with compromised immune systems, subverts 26S proteasome function for the degradation of key cellular factors capable of restricting viral replication (14)(15)(16)(17)(18)(19)(20). Upon entry, HCMV virions deposit the viral tegument protein pp71 into the cell, where it commandeers the 26S proteasome to degrade cellular transcriptional corepressors Daxx, BclAF-1, retinoblastoma protein (Rb), p107, and p130 to promote viral gene expression (16,18,19,(21)(22).…”

mentioning

confidence: 99%

The 19S Proteasome Activator Promotes Human Cytomegalovirus Immediate Early Gene Expression through Proteolytic and Nonproteolytic Mechanisms

Winkler

Kalejta

2014

J Virol

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Proteasomes are large, multisubunit complexes that support normal cellular activities by executing the bulk of protein turnover. During infection, many viruses have been shown to promote viral replication by using proteasomes to degrade cellular factors that restrict viral replication. For example, the human cytomegalovirus (HCMV) pp71 protein induces the proteasomal degradation of Daxx, a cellular transcriptional repressor that can silence viral immediate early (IE) gene expression. We previously showed that this degradation requires both the proteasome catalytic 20S core particle (CP) and the 19S regulatory particle (RP). The 19S RP associates with the 20S CP to facilitate protein degradation but also plays a 20S CP-independent role promoting transcription. Here, we present a nonproteolytic role of the 19S RP in HCMV IE gene expression. We demonstrate that 19S RP subunits are recruited to the major immediate early promoter (MIEP) that directs IE transcription. Depletion of 19S RP subunits generated a defect in RNA polymerase II elongation through the MIE locus during HCMV infection. Our results reveal that HCMV commandeers proteasome components for both proteolytic and nonproteolytic roles to promote HCMV lytic infection. IMPORTANCEProteasome inhibitors decrease or eliminate 20S CP activity and are garnering increasing interest as chemotherapeutics. However, an increasing body of evidence implicates 19S RP subunits in important proteolytic-independent roles during transcription. Thus, pharmacological inhibition of the 20S CP as a means to modulate proteasome function toward therapeutic effect is an incomplete capitalization on the potential of this approach. Here, we provide an additional example of nonproteolytic 19S RP function in promoting HCMV transcription. These data provide a novel system with which to study the roles of different proteasome components during transcription, a rationale for previously described shifts in 19S RP subunit localization during HCMV infection, and a potential therapeutic intervention point at a pre-immediate early stage for the inhibition of HCMV infection. Proteasomes mediate the majority of cellular protein turnover, promoting multiple signaling pathways, cell cycle progression, and general cellular homeostasis (1). These large, multisubunit complexes also permit immune detection of virally infected cells by generating the foreign peptides displayed by major histocompatibility complexes (MHCs) (2). In addition to this prominent antiviral role, proteasomes promote viral infection through the degradation of cellular factors that restrict viral infection. The dichotomous roles of proteasomes during viral infection and their general requirement for cellular health necessitate that viruses modulate proteasomal activities in a precise manner to promote viral infection (3-5).The barrel-like 20S catalytic core particle (CP) of the proteasome, consisting of two sets of seven distinct alpha (␣1 to ␣7) and beta (␤1 to ␤7) subunits, contains the proteolytic components responsibl...

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Human Cytomegalovirus Inhibits Apoptosis by Proteasome-Mediated Degradation of Bax at Endoplasmic Reticulum-Mitochondrion Contacts

Cited by 39 publications

References 80 publications

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central

The 19S Proteasome Activator Promotes Human Cytomegalovirus Immediate Early Gene Expression through Proteolytic and Nonproteolytic Mechanisms

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