RIP1/RIP3 Binding to HSV-1 ICP6 Initiates Necroptosis to Restrict Virus Propagation in Mice

Huang, Zhenguo; Wu, Shuodong; Liang, Yaoji; Zhou, Xiaojuan; Chen, Wanze; Liu, Lisheng; Wu, Jianfeng; Zhuang, Qiuyu; Chen, Changan; Li, Jingxian; Zhong, Chuan-Qi; Xia, Weixiang; Zhou, Rongbin; Zheng, Chunfu; Han, Jiahuai

doi:10.1016/j.chom.2015.01.002

Cited by 224 publications

(258 citation statements)

References 32 publications

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“…Thus, viruses can trigger necroptosis, and RIP3-deficient mice are more susceptible to infection by a number of pathogenic viruses including herpes simplex virus 1 55 and murine cytomegalovirus, 56 supporting the idea that necroptosis can restrain viral infection. In accord with this speculation, there is ample evidence that pathogenic viruses can manipulate RIP3-dependent necroptosis, 57,58 perhaps as a strategy for immune escape.…”

Section: Discussionmentioning

confidence: 88%

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Yang¹,

Ma²,

Guo³

et al. 2016

OncoImmunology

151

145

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Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 ¡/¡ and Mlkl ¡/¡ tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 ¡/¡ and Mlkl ¡/¡ cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

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Section: Discussionmentioning

confidence: 88%

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Yang¹,

Ma²,

Guo³

et al. 2016

OncoImmunology

151

145

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“…Interestingly, a species-specific necroptosis inhibition has been reported for the herpes simplex virus 1 (HSV-1) ICP6 and the HSV-2 ICP10 proteins: ICP6 and ICP10 inhibit necroptosis in human but not in mouse cells (45,46,53). ICP6, ICP10, and M45 are homologous proteins, and all three possess a RHIM (54), which is required for the inhibition of RIP3-dependent necroptosis (29,45,46). As MC159 does not appear to have a RHIM, its necroptosis-inhibiting activity is likely to operate through a different mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Although human cells are not permissive for MCMV replication, MCMV-infected human cells usually express viral immediate early and early proteins (44). We decided to use human HT-29 colon carcinoma cells, as these cells have been used previously for analysis of viral necroptosis inhibitors (45)(46)(47). First, we infected HT-29 cells with MCMV and analyzed the expression of the immediate early protein IE1 and the early protein M45 at different times postinfection by immunoblotting.…”

Section: Mc159 Inhibits Apoptosis But Does Not Block Necroptosis In Mmentioning

confidence: 99%

Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Hüttmann

Krause

Schommartz

et al. 2016

J Virol

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Molluscum contagiosum virus (MCV) gene IMPORTANCEMCV is a human-pathogenic poxvirus that cannot be propagated in cell culture or laboratory animals. Therefore, MCV gene products have been studied predominantly in cells expressing individual viral genes. In this study, we analyzed the function of the MCV gene MC159 by expressing it from a different virus and comparing its functions to those of two well-characterized MCMV genes. In this system, MC159 displayed some but not all of the previously described functions, suggesting that the functions of a viral gene depend on the conditions under which it is expressed. Until a cell culture system for the analysis of MCV becomes available, it might be necessary to analyze MCV genes in several different systems to extrapolate their biological importance. Molluscum contagiosum virus (MCV) is a worldwide-occurring poxvirus that replicates exclusively in humans (1). Seroprevalence ranges from up to 39% in immunocompetent individuals (2, 3), affecting mostly children and young adults, to 91% in HIV-infected patients (2). Molluscum contagiosum (MC) is an infectious disease of the skin characterized by small, benign papular skin lesions that usually regress after a few months. However, in immunocompromised patients MC can become much more severe, with extensive lesions that are difficult to treat (1). This indicates the important role of the host immune system in confining and eliminating the infection.Despite its importance as a human pathogen, MCV has not been studied extensively due to technical difficulties. There is neither a cell culture system suitable for the propagation of MCV nor an animal model that recapitulates MCV replication. Therefore, individual MCV genes were studied either by using transient transfection or by expression in a recombinant vaccinia virus (VACV) as a surrogate virus (4).MCV expresses several immune-modulating proteins that are thought to contribute to the persistence of the virus (4, 5). One of these proteins, MC159, has been identified as a viral FLICE-like inhibitory protein (vFLIP) (6) due to its structural and functional similarity to cellular FLIP (cFLIP) (7). Although vFLIPs have not been found in poxviruses other than MCV, they are present in several gammaherpesviruses (6,8,9). MC159 interacts with Fasassociated protein with death domain (FADD) and procaspase-8 (formerly known as FADD-like interleukin-1␤-converting enzyme [FLICE]) and prevents Fas-and tumor necrosis factor alpha (TNF-␣)-induced apoptosis (6,(8)(9)(10). However, if caspase-8 is inhibited, receptor interacting protein kinase 1 (RIP1, RIPK1) is not cleaved and recruits RIP3 (RIPK3), initiating a pathway lead-

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“…M45/vIRA mutant MCMV triggers programmed necrosis by inducing an interaction between RIP3 and the DNA-dependent activator of IFN regulatory factor (DAI) (24). Unlike VV and MCMV, herpes simplex virus 1 (HSV-1) infection naturally activates mouse RIP3 (mRIP3)/mMLKL-dependent necrosis in mouse cells independently of TNFR, TLR3, and DAI (25,26). During HSV-1 infection, RIP3 is activated by the assembly of a complex with the RHIM-containing viral protein ICP6, the large subunit (R1) of ribonucleotide reductase (RR), leading to MLKL activation and necrosis of host cells (25,26).…”

mentioning

confidence: 99%

“…Unlike VV and MCMV, herpes simplex virus 1 (HSV-1) infection naturally activates mouse RIP3 (mRIP3)/mMLKL-dependent necrosis in mouse cells independently of TNFR, TLR3, and DAI (25,26). During HSV-1 infection, RIP3 is activated by the assembly of a complex with the RHIM-containing viral protein ICP6, the large subunit (R1) of ribonucleotide reductase (RR), leading to MLKL activation and necrosis of host cells (25,26). RIP3-deficient mice showed severely impaired control of HSV-1 replication and pathogenesis (25).…”

mentioning

confidence: 99%

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1

Chen

et al. 2016

J Virol

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Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. IMPORTANCE This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells.The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV. N ecrotic cell death characterized by the disruption of the plasma membrane has been observed in a variety of physiological and pathological processes, including in mammalian development, in tissue damage, and in pathogen infection (1-3). Inhibition of apoptosis is known to facilitate programmed necrosis in cells. Proteins of the tumor necrosis factor (TNF) family of cytokines, including TNF-␣, TRAIL (TNF-related apoptosis-inducing ligand), and FasL, are classic inducers of programmed necrosis, also known as necroptosis (4). In TNF-␣-triggered necrosis, receptor-interacting protein kinase 1 (RIP1) (5) forms a protein complex, called the necrosome (6), with receptor-interacting protein kinase 3 (RIP3) (7-9) through the RIP homotypic interaction motif (RHIM) domains of both proteins (10). Deubiquitination of RIP1 by cylindromatosis (CYLD) is required to mediate necrosome formation and activation (11,12). Active RIP3 subsequently phosphorylates its substrate, mixed-lineage kinase domain-like protein (MLKL), to trigger membrane localization of MLKL and downstream events for the induction of membrane rupture (13)(14)(15)(16)(17).Additionally, the recognition of pathogen-associated molecular patterns by the Toll-like receptor (TLR) proteins triggers programmed necrosis. TLR3 and TLR4 specifically recognize, respectively, viral double-stranded RNA (dsRNA) [or a synthesized analog of dsRNA poly(I·C)], and bacteria lipop...

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RIP1/RIP3 Binding to HSV-1 ICP6 Initiates Necroptosis to Restrict Virus Propagation in Mice

Cited by 224 publications

References 32 publications

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1

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