scholarly journals Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

2015 ◽  
Vol 89 (13) ◽  
pp. 6646-6655 ◽  
Author(s):  
Ran Xiong ◽  
Ping Rao ◽  
Seil Kim ◽  
Michelle Li ◽  
Xiangshu Wen ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Immune System ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Immune Evasion ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 bothin vitroand in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses.IMPORTANCEHerpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein KIF3A as a cellular substrate phosphorylated by US3, and this phosphorylation event mediates US3-induced immune evasion.

scholarly journals RIG-I-Mediated STING Upregulation Restricts Herpes Simplex Virus 1 Infection

2016 ◽  
Vol 90 (20) ◽  
pp. 9406-9419 ◽  
Author(s):  
Yiliu Liu ◽  
Marie-Line Goulet ◽  
Alexandre Sze ◽  
Samar Bel Hadj ◽  
Sidi Mehdi Belgnaoui ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Immune System ◽  
Herpes Simplex ◽  
Innate Immune System ◽  
Innate Immune ◽  
Herpes Simplex Virus 1 ◽  
Dna And Rna ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTSTING has emerged in recent years as a key player in orchestrating innate immune responses to cytosolic DNA and RNA derived from pathogens. However, the regulation of STING still remains poorly defined. In the present study, we investigated the mechanism of the regulation of STING expression in relation to the RIG-I pathway. Our data show that signaling through RIG-I induces STING expression at both the transcriptional and protein levels in various cell types. STING induction by the RIG-I agonist 5′triphosphorylated RNA (5′pppRNA) was recognized to be a delayed event resulting from an autocrine/paracrine mechanism. Indeed, cotreatment with tumor necrosis factor alpha and type I/II interferon was found to have a synergistic effect on the regulation of STING expression and could be potently decreased by impairing NF-κB and/or STAT1/2 signaling. STING induction significantly contributed to sustainment of the immune signaling cascade following 5′pppRNA treatment. Physiologically, this cross talk between the RNA- and DNA-sensing pathways allowed 5′pppRNA to efficiently block infection by herpes simplex virus 1 (HSV-1) bothin vitroandin vivoin a STING-dependent fashion. These observations demonstrate that STING induction by RIG-I signaling through the NF-κB and STAT1/2 cascades is essential for RIG-I agonist-mediated HSV-1 restriction.IMPORTANCEThe innate immune system represents the first line of defense against invading pathogens. The dysregulation of this system can result in failure to combat pathogens, inflammation, and autoimmune diseases. Thus, precise regulation at each level of the innate immune system is crucial. Recently, a number of studies have established STING to be a central molecule in the innate immune response to cytosolic DNA and RNA derived from pathogens. Here, we describe the regulation of STING via RIG-I-mediated innate immune sensing. We found that STING is synergistically induced via proinflammatory and antiviral cytokine cascades. In addition, we show thatin vivoprotection against herpes simplex virus 1 (HSV-1) by a RIG-I agonist required STING. Our study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING.

scholarly journals Species-Specific Deamidation of RIG-I Reveals Collaborative Action between Viral and Cellular Deamidases in HSV-1 Lytic Replication

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Huichao Huang ◽  
Jun Zhao ◽  
Ting-Yu Wang ◽  
Shu Zhang ◽  
Yuzheng Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Host Defense ◽  
Immune Evasion ◽  
Herpes Simplex Virus 1 ◽  
Species Specific ◽  
Simplex Virus ◽  
Phosphoribosylpyrophosphate Amidotransferase ◽  
Hsv 1

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is a sensor that recognizes cytosolic double-stranded RNA derived from microbes to induce host immune response. Viruses, such as herpesviruses, deploy diverse mechanisms to derail RIG-I-dependent innate immune defense. In this study, we discovered that mouse RIG-I is intrinsically resistant to deamidation and evasion by herpes simplex virus 1 (HSV-1). Comparative studies involving human and mouse RIG-I indicate that N495 of human RIG-I dictates species-specific deamidation by HSV-1 UL37. Remarkably, deamidation of the other site, N549, hinges on that of N495, and it is catalyzed by cellular phosphoribosylpyrophosphate amidotransferase (PPAT). Specifically, deamidation of N495 enables RIG-I to interact with PPAT, leading to subsequent deamidation of N549. Collaboration between UL37 and PPAT is required for HSV-1 to evade RIG-I-mediated antiviral immune response. This work identifies an immune regulatory role of PPAT in innate host defense and establishes a sequential deamidation event catalyzed by distinct deamidases in immune evasion. IMPORTANCE Herpesviruses are ubiquitous pathogens in human and establish lifelong persistence despite host immunity. The ability to evade host immune response is pivotal for viral persistence and pathogenesis. In this study, we investigated the evasion, mediated by deamidation, of species-specific RIG-I by herpes simplex virus 1 (HSV-1). Our findings uncovered a collaborative and sequential action between viral deamidase UL37 and a cellular glutamine amidotransferase, phosphoribosylpyrophosphate amidotransferase (PPAT), to inactivate RIG-I and mute antiviral gene expression. PPAT catalyzes the rate-limiting step of the de novo purine synthesis pathway. This work describes a new function of cellular metabolic enzymes in host defense and viral immune evasion.

scholarly journals Differences in the Regulatory and Functional Effects of the Us3 Protein Kinase Activities of Herpes Simplex Virus 1 and 2

2009 ◽  
Vol 83 (22) ◽  
pp. 11624-11634 ◽  
Author(s):  
Tomomi Morimoto ◽  
Jun Arii ◽  
Michiko Tanaka ◽  
Tetsutaro Sata ◽  
Hiroomi Akashi ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinases ◽  
Kinase Activity ◽  
Viral Envelope ◽  
Cell Surface Expression ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Us3 protein kinases encoded by herpes simplex virus 1 (HSV-1) and 2 (HSV-2) are serine/threonine protein kinases and play critical roles in viral replication and pathogenicity in vivo. In the present study, we investigated differences in the biological properties of HSV-1 and HSV-2 Us3 protein kinases and demonstrated that HSV-2 Us3 did not have some of the HSV-1 Us3 kinase functions, including control of nuclear egress of nucleocapsids, localization of UL31 and UL34, and cell surface expression of viral envelope glycoprotein B. In agreement with the observations that HSV-2 Us3 was less important for these functions, the effect of HSV-2 Us3 kinase activity on virulence in mice following intracerebral inoculation was much lower than that of HSV-1 Us3. Furthermore, we showed that alanine substitution in HSV-2 Us3 at a site (aspartic acid at position 147) corresponding to one that can be autophosphorylated in HSV-1 Us3 abolished HSV-2 Us3 kinase activity. Thus, the regulatory and functional effects of Us3 kinase activity are different between HSV-1 and HSV-2.

scholarly journals Herpes Simplex Virus 1 Specifically Targets Human CD1d Antigen Presentation To Enhance Its Pathogenicity

2018 ◽  
Vol 92 (22) ◽  
Author(s):  
Ping Rao ◽  
Xiangshu Wen ◽  
Jae Ho Lo ◽  
Seil Kim ◽  
Xin Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Immune System ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Cell Function ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) is one of the most prevalent herpesviruses in humans and represents a constant health threat to aged and immunocompromised populations. How HSV-1 interacts with the host immune system to efficiently establish infection and latency is only partially known. CD1d-restricted NKT cells are a critical arm of the host innate immune system and play potent roles in anti-infection and antitumor immune responses. We discovered previously that upon infection, HSV-1 rapidly and efficiently downregulates CD1d expression on the cell surface and suppresses the function of NKT cells. Furthermore, we identified the viral serine/threonine protein kinase US3 as a major viral factor downregulating CD1d during infection. Interestingly, neither HSV-1 nor its US3 protein efficiently inhibits mouse CD1d expression, suggesting that HSV-1 has coevolved with the human immune system to specifically suppress human CD1d (hCD1d) and NKT cell function for its pathogenesis. This is consistent with the fact that wild-type mice are mostly resistant to HSV-1 infection. On the other hand,in vivoinfection of CD1d-humanized mice (hCD1d knock-in mice) showed that HSV-1 can indeed evade hCD1d function and establish infection in these mice. We also report here that US3-deficient viruses cannot efficiently infect hCD1d knock-in mice but infect mice lacking all NKT cells at a higher efficiency. Together, these studies supported HSV-1 evasion of human CD1d and NKT cell function as an important pathogenic factor for the virus. Our results also validated the potent roles of NKT cells in antiherpesvirus immune responses and pointed to the potential of NKT cell ligands as adjuvants for future vaccine development.IMPORTANCEHerpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We reported previously that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule, CD1d, so as to evade the antiviral function of NKT cells. Here we demonstrated that the virus has coevolved with the human CD1d and NKT cell system and that NKT cells indeed play potent roles in anti-HSV immune responses. These studies point to the great potential of exploring NKT cell ligands as adjuvants for HSV vaccines.

scholarly journals Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔUS3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

2006 ◽  
Vol 80 (7) ◽  
pp. 3341-3348 ◽  
Author(s):  
Luca Benetti ◽  
Bernard Roizman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Protein Kinase B ◽  
Mutant Virus ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The product of the herpes simplex virus 1 (HSV-1) US3 gene is a multifunctional serine-threonine protein kinase that can block apoptosis induced by proapoptotic cellular proteins, exogenous agents, or replication-defective viruses. Earlier studies showed that the US3 kinase activates and functionally overlaps cellular protein kinase A (PKA). In this study we examined the status of phosphatidylinositol 3-kinase [PI(3)K] and of its effector, protein kinase B/Akt (PKB/Akt), a component of a major pathway of mammalian antiapoptotic signaling systems. We report the following. (i) Infection of target cells with HSV-1 induces transient phosphorylation of serine 473 of PKB/Akt early in infection, with a mechanism that is dependent on PI(3)K. Inhibition of PI(3)K induced apoptosis in mock-infected or ΔUS3 mutant-virus-infected but not in wild-type-virus-infected cells and reduced the accumulation of specific viral gene products, including the US3 protein kinase, but had a marginal effect on virus yields. (ii) At later times after infection, the total amounts of PKB/Akt decreased and phosphorylated PKB/Akt forms disappeared in a US3-dependent and protein phosphatase 2A-independent manner. (iii) Activation of PKA by forskolin did not mediate significant dephosphorylation of PKB/Akt. Our results are consistent with the model that PKB/Akt is activated early in infection and acts to block apoptosis in infected cells prior to the accumulation of US3 protein kinase and that it persists and continues to function as an antiapoptotic protein in the absence of US3 but becomes redundant or even inimical once US3 protein kinase accumulates in effective amounts.

scholarly journals Herpes Simplex Virus 1 Protein Kinase US3 Hyperphosphorylates p65/RelA and Dampens NF-κB Activation

2014 ◽  
Vol 88 (14) ◽  
pp. 7941-7951 ◽  
Author(s):  
Kezhen Wang ◽  
Liwen Ni ◽  
Shuai Wang ◽  
Chunfu Zheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Immune Responses ◽  
Kinase Activity ◽  
Nuclear Translocation ◽  
Interleukin 8 ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTNuclear factor κB (NF-κB) plays important roles in innate immune responses by regulating the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation, and survival. To survive in the host cells, viruses have evolved multiple strategies to evade and subvert the host immune response. Herpes simplex virus 1 (HSV-1) bears a large DNA genome, with the capacity to encode many different viral proteins to counteract the host immune responses. In the present study, we demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 was also shown to hyperphosphorylate p65 at serine 75 and block its nuclear translocation. Two US3 mutants, K220M and D305A, still interacted with p65; however, they could not hyperphosphorylate p65, indicating that the kinase activity of US3 was indispensable for the function. The attenuation of NF-κB activation by HSV-1 US3 protein kinase may represent a critical adaptation to enable virus persistence within the host.IMPORTANCEThis study demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 hyperphosphorylated p65 at serine 75 to inhibit NF-κB activation. The kinase activity of US3 was indispensable for its hyperphosphorylation of p65 and abrogation of the nuclear translocation of p65. The present study elaborated a novel mechanism of HSV-1 US3 to evade the host innate immunity.

scholarly journals Regulation of the Catalytic Activity of Herpes Simplex Virus 1 Protein Kinase Us3 by Autophosphorylation and Its Role in Pathogenesis

2009 ◽  
Vol 83 (11) ◽  
pp. 5773-5783 ◽  
Author(s):  
Ken Sagou ◽  
Takahiko Imai ◽  
Hiroshi Sagara ◽  
Masashi Uema ◽  
Yasushi Kawaguchi
Keyword(s):  
Catalytic Activity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Viral Replication ◽  
Kinase Activity ◽  
Herpes Simplex Virus 1 ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Us3 is a serine/threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). We recently identified serine at Us3 position 147 (Ser-147) as a physiological phosphorylation site of Us3 (A. Kato, M. Tanaka, M. Yamamoto, R. Asai, T. Sata, Y. Nishiyama, and Y. Kawaguchi, J. Virol. 82:6172-6189, 2008). In the present study, we investigated the effects of phosphorylation of Us3 Ser-147 on regulation of Us3 catalytic activity in infected cells and on HSV-1 pathogenesis. Our results were as follows. (i) Only a small fraction of Us3 purified from infected cells was phosphorylated at Ser-147. (ii) Us3 phosphorylated at Ser-147 purified from infected cells had significantly higher kinase activity than Us3 not phosphorylated at Ser-147. (iii) Phosphorylation of Us3 Ser-147 in infected cells was dependent on Us3 kinase activity. (iv) Replacement of Us3 Ser-147 by alanine significantly reduced viral replication in the mouse cornea and the development of herpes stromal keratitis and periocular skin disease in mice. These results indicated that Us3 catalytic activity is tightly regulated by autophosphorylation of Ser-147 in infected cells and that regulation of Us3 activity by autophosphorylation appeared to play a critical role in viral replication in vivo and in HSV-1 pathogenesis.

scholarly journals Identification of a Physiological Phosphorylation Site of the Herpes Simplex Virus 1-Encoded Protein Kinase Us3 Which Regulates Its Optimal Catalytic Activity In Vitro and Influences Its Function in Infected Cells

2008 ◽  
Vol 82 (13) ◽  
pp. 6172-6189 ◽  
Author(s):  
Akihisa Kato ◽  
Michiko Tanaka ◽  
Mayuko Yamamoto ◽  
Risa Asai ◽  
Tetsutaro Sata ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Herpes Simplex Virus 1 ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Us3 is a serine/threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). Here, we report the identification of a physiological Us3 phosphorylation site on serine at position 147 (Ser-147) which regulates its protein kinase activity in vitro. Moreover, mutation of this site influences Us3 function, including correct localization of the enzyme and induction of the usual morphological changes in HSV-1-infected cells. These conclusions are based on the following observations: (i) in in vitro kinase assays, a domain of Us3 containing Ser-147 was specifically phosphorylated by Us3 and protein kinase A, while a mutant domain in which Ser-147 was replaced with alanine was not; (ii) in vitro, alanine replacement of Ser-147 (S147A) in Us3 resulted in significant impairment of the kinase activity of the purified molecule expressed in a baculovirus system; (iii) phosphorylation of Ser-147 in Us3 tagged with the monomeric fluorescent protein (FP) VenusA206K (VenusA206K-Us3) from Vero cells infected with a recombinant HSV-1 encoding VenusA206K-Us3 was specifically detected using an antibody that recognizes phosphorylated serine or threonine residues with arginine at the −3 and −2 positions; and (iv) the S147A mutation influenced some but not all Us3 functions, including the ability of the protein to localize itself properly and to induce wild-type cytopathic effects in infected cells. Our results suggest that some of the regulatory activities of Us3 in infected cells are controlled by phosphorylation at Ser-147.

Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

1995 ◽  
Vol 53 ◽  
pp. 840-841
Author(s):  
Z. Hong Zhou ◽  
Jing He ◽  
Joanita Jakana ◽  
J. D. Tatman ◽  
Frazer J. Rixon ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
3D Structure ◽  
Structure Study ◽  
Herpes Simplex Virus 1 ◽  
Shell Proteins ◽  
Life Threatening ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

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