Two Overlapping Regions within the N-Terminal Half of the Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Facilitate the Degradation and Dissociation of PML and Dissociation of Sp100 from ND10

Lanfranca, Mirna Perusina; Mostafa, Heba H.; Davido, David J.

doi:10.1128/jvi.02304-13

Cited by 15 publications

(11 citation statements)

References 73 publications

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“…10 for reasons of completeness and will not be discussed further here. The RING finger itself has been extensively studied previously, while a recent paper implicates the sequences immediately downstream of the RING finger as also being involved in PML degradation (38). Outside all of these regions, the alignment between the ICP0 proteins of HSV-1, HSV-2, and HVB taken together shows considerably less sequence identity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection

Everett

Boutell

Pheasant

et al. 2014

J Virol

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Herpes simplex virus type 1 immediate-early protein ICP0 is an E3 ubiquitin ligase of the RING finger class that degrades several cellular proteins during infection. This activity is essential for its functions in stimulating efficient lytic infection and productive reactivation from latency. ICP0 targets a number of proteins that are modified by the small ubiquitin-like SUMO family of proteins, and it includes a number of short sequences that are related to SUMO interaction motifs (SIMs). Therefore, ICP0 has characteristics that are related to those of cellular SUMO-targeted ubiquitin ligase enzymes. Here, we analyze the impact of mutation of a number of SIM-like sequences (SLSs) within ICP0 on HSV-1 replication and gene expression and their requirement for ICP0-mediated degradation of both sumoylated and unmodified promyelocytic leukemia (PML) and other sumoylated cellular proteins. One SLS in the central portion of the ICP0 sequence (SLS4) was found to be absolutely required for targeting cellular sumoylated species in general and sumoylated forms of PML other than those of PML isoform I. Mutation of a group of SLSs in the C-terminal quarter of ICP0 also reduced ICP0-mediated degradation of sumoylated PML in a cooperative manner. Although mutation of individual SLSs caused only modest decreases in viral replication, combined mutation of SLS4 with SLS sequences in the C-terminal quarter of the protein reduced plaque formation efficiency by up to two orders of magnitude. These results provide further evidence that the biological activities of ICP0 are connected with host cell sumoylation events. IMPORTANCEHerpes simplex virus type 1 protein ICP0 plays important roles in regulating the initial stages of lytic infection and productive reactivation from latency. ICP0 mediates its effects through inducing the degradation of cellular proteins that have repressive effects on viral gene expression. An increasing number of cellular proteins are known to be sensitive to ICP0-mediated degradation; therefore, it is important to understand how ICP0 selects its substrates for degradation. This study identifies sequence motifs within ICP0 that are involved in targeting cellular proteins that are modified by the SUMO family of ubiquitin-like proteins and describes how mutation of combinations of these motifs causes a 100-fold defect in viral infectivity. Herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0, a member of the RING finger class of E3 ubiquitin ligases, is required for efficient lytic infection and productive reactivation from latency (1-3). These biological functions of ICP0 require its biochemical ubiquitin ligase activity that results in the degradation of several cellular proteins. While these basic aspects of ICP0 have been firmly established, several questions remain concerning the mechanisms by which ICP0 selects its substrates for degradation and the significance of individual substrates for the outcome of infection. It has long been established that ICP0 initially localizes to cellular...

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Section: Discussionmentioning

confidence: 99%

Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection

Everett

Boutell

Pheasant

et al. 2014

J Virol

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“…During HSV-1 infection, viral protein ICP0 induces the degradation of PML, thereby disrupting nuclear domain 10 (ND10) 30 , 31 . It has been uncovered that a portion of the C terminus (amino acids 633 to 767), the nuclear localization signal (NLS) and two overlapping regions within the central N-terminal portion of ICP0 (residues 212 to 311) facilitate its dissociation and degradation of PML 69 . In our study, we also observed decreased expression of PML protein after HSV-1 infection (Figure 5 , Figures S6 -8).…”

Section: Discussionmentioning

confidence: 99%

Autophagic degradation of PML promotes susceptibility to HSV-1 by stress-induced Corticosterone

Luo

Yan

et al. 2020

Theranostics

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Rationale: Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that can cause a variety of clinical syndromes including mucocutaneous disease and HSV-1 encephalitis (HSE). Here, we characterize the molecular mechanisms underlying the susceptibility to HSV-1 under stressful conditions. Methods: Restraint stress and corticosterone (CORT, a primary stress hormone) were respectively used to establish HSV-1 susceptible model in vivo and in vitro . Viral titers were determined by plaque assay. Western blotting, immunofluorescence, transmission electron microscopy (TEM), qRT-PCR, H&E staining, IHC staining and flow cytometry were employed to evaluate virus-related protein expressions and detect the activation of autophagy. Loss- and gain-function assays, co-immunoprecipitation (co-IP) technique and autophagy agonist/antagonist treatments were applied in mechanistic experiments. Results: Restraint stress increased the susceptibility of mouse brain to HSV-1. Similarly, CORT treatment enhanced the susceptibility of neural cells to HSV-1. Furthermore, PML protein level in HSV-1 infected brain tissues and neural cells was remarkably decreased by stress treatment in vivo or CORT treatment in vitro , while its transcriptional level was not affected. Notably, a striking decline in protein expressions of ICP27 and gB was observed in PML-overexpressing cells, which was reversed by CORT treatment. By contrast, protein expression of gB was increased by knockdown with si- PML in virus-infected SH-SY5Y cells. We further discovered that CORT-driven PML degradation was dependent on the activation of autophagy in a ULK1-independent manner, rather than proteasome pathway. Bafilomycin A1 (BaF1) attenuated the augmentation effect of CORT on HSV-1 infection. The expressions of viral proteins were reduced in LC3-depleted cells, and the degradation of PML by CORT-induced autophagy was prevented in cells with LC3 knockdown by RNAi. Interestingly, PML was revealed to interact with the autophagic cargo receptor P62 and the autophagic effector protein LC3. Additionally, CORT failed to increase gB protein level when PML was silenced, providing direct evidence linking autophagic degradation of PML and CORT-induced virus susceptibility. Conclusion: Our results revealed that restraint stress/CORT increased HSV-1 susceptibility by delivering PML into autolysosomes for degradation. The results obtained from in vitro and in viv o models not only demonstrated the adverse effects of stress on HSV-1 infection, but also systematically investigated the underlying molecular mechanisms. These discoveries broaden our understanding of the interplay between host and viruses, and a comprehensive understanding of the role of autophagy in viral infection will provide information for future development of innovat...

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“…Several ND10 constituent proteins, including PML (promyelocytic leukemia), Sp100 (speckled protein of 100 kDa), hDaxx (human death domain-associated protein 6), and ATRX (alpha thalassemia/mental retardation syndrome X-linked) can limit the replication of an ICP0 null HSV-1 mutant [ 41 , 42 , 43 ]. Upon viral infection, ND10-associated proteins are recruited to the incoming viral genome; however, ICP0’s E3 Ub ligase activity promotes the disruption of ND10 (partially through a C-terminal domain, Figure 1 ) by mediating the proteolysis (directly or indirectly) of PML and Sp100 [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ] or dissociating hDaxx and ATRX [ 53 ] from ND10. The disruption of ND10s by ICP0 alleviates the repressive functions of ND10-associated proteins and stimulates viral transcription.…”

Section: Icp0 Counteracts the Intrinsic Antiviral Resistance Of Ndmentioning

confidence: 99%

HSV-1 ICP0: An E3 Ubiquitin Ligase That Counteracts Host Intrinsic and Innate Immunity

Lanfranca

Mostafa

Davido

2014

Cells

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The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the proteasomal degradation of several cellular targets, allowing the virus to counteract different cellular intrinsic and innate immune responses. In this review, we will focus on how ICP0’s E3 ubiquitin ligase activity inactivates the host intrinsic defenses, such as nuclear domain 10 (ND10), SUMO, and the DNA damage response to HSV-1 infection. In addition, we will examine ICP0’s capacity to impair the activation of interferon (innate) regulatory mediators that include IFI16 (IFN γ-inducible protein 16), MyD88 (myeloid differentiation factor 88), and Mal (MyD88 adaptor-like protein). We will also consider how ICP0 allows HSV-1 to evade activation of the NF-κB (nuclear factor kappa B) inflammatory signaling pathway. Finally, ICP0’s paradoxical relationship with USP7 (ubiquitin specific protease 7) and its roles in intrinsic and innate immune responses to HSV-1 infection will be discussed.

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Two Overlapping Regions within the N-Terminal Half of the Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Facilitate the Degradation and Dissociation of PML and Dissociation of Sp100 from ND10

Cited by 15 publications

References 73 publications

Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection

Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection

Autophagic degradation of PML promotes susceptibility to HSV-1 by stress-induced Corticosterone

HSV-1 ICP0: An E3 Ubiquitin Ligase That Counteracts Host Intrinsic and Innate Immunity

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