Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection

Challa, Sreerupa; Woelfel, Melissa A.; Guildford, Melissa J.; Moquin, David M.; Chan, Francis Ka‐Ming

doi:10.1128/jvi.00983-10

Cited by 26 publications

(24 citation statements)

References 58 publications

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“…Nevertheless, MC159, MC160, or cFLIP L expression greatly decreased IFN-β enhancer-controlled luciferase activity in comparison with cells transfected with empty vector, regardless of the presence or absence of the p65 subunit of NF-κB in MEFs. It should also be mentioned that a recent report shows that MC159 activates NF-κB (48). However, the overexpression of MC159, or any other FLIP, did not induce IFN-β enhancer activity in both cell types tested here.…”

Section: Resultsmentioning

confidence: 45%

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Randall

Biswas

Selen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis, NF-κB activation, and IRF3 activation are a triad of intrinsic immune responses that play crucial roles in the pathogenesis of infectious diseases, cancer, and autoimmunity. FLIPs are a family of viral and cellular proteins initially found to inhibit apoptosis and more recently to either up-or down-regulate NF-κB. As such, a broad role for FLIPs in disease regulation is postulated, but exactly how a FLIP performs such multifunctional roles remains to be established. Here we examine FLIPs (MC159 and MC160) encoded by the molluscum contagiosum virus, a dermatotropic poxvirus causing skin infections common in children and immunocompromised individuals, to better understand their roles in viral pathogenesis. While studying their molecular mechanisms responsible for NF-κB inhibition, we discovered that each protein inhibited IRF3-controlled luciferase activity, identifying a unique function for FLIPs. MC159 and MC160 each inhibited TBK1 phosphorylation, confirming this unique function. Surprisingly, MC159 coimmunoprecipitated with TBK1 and IKKe but MC160 did not, suggesting that these homologs use distinct molecular mechanisms to inhibit IRF3 activation. Equally surprising was the finding that the FLIP regions necessary for TBK1 inhibition were distinct from those MC159 or MC160 regions previously defined to inhibit NF-κB or apoptosis. These data reveal previously unappreciated complexities of FLIPs, and that subtle differences within the conserved regions of FLIPs possess distinct molecular and structural fingerprints that define crucial differences in biological activities. A future comparison of mechanistic differences between viral FLIP proteins can provide new means of precisely manipulating distinct aspects of intrinsic immune responses.host-pathogen interactions | immune evasion I FN-β provides an important defense against viral infections (1, 2). The pathway leading to IFN-β production is well characterized. By-products of viral infection, such as dsRNA, are detected by upstream cellular sensors, including retinoic acidinducible gene 1 (RIG-I), melanoma differentiation-associated factor gene 5 (MDA5), and STING. RIG-I and MDA5 proteins then interact with mitochondrial antiviral signaling (MAVS) adaptor protein to trigger MAVS activation (3-8). The TNF receptor-associated factor 3 (TRAF3) adaptor protein is recruited to this complex, resulting in the activation of the kinase complex TANK-binding kinase 1 (TBK1)-IκB kinase e (IKKe) (9-11). Alternatively, the STING molecule activates TBK1-IKKe (12, 13). In either case, TBK1-IKKe phosphorylates and activates IFN regulatory factor (IRF) transcription factor proteins (11), which migrate to the nucleus to bind to the IFN-β enhancer. IFN-β is secreted and binds to the IFN receptor (IFNR). This initiates a second signaling cascade in infected and neighboring cells, which promotes expression of IFN-α and IFN-stimulated genes whose products contribute to an antiviral state.Identification of the above members of the IFN-β signal transduction pathway also resul...

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Section: Resultsmentioning

confidence: 45%

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Randall

Biswas

Selen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…On the other hand, MCMV replicates its DNA and transcribes its genes in the nucleus, not in the cytoplasm as MCV does, and MCMV is a mouse virus, whereas MCV is a human virus. However, MC159 functions have previously been characterized in transfected mouse cells (18,50) or in transgenic mice (19,49), suggesting that MC159 functions are not generally restricted to human cells. Nevertheless, one could argue that VACV is more closely related to MCV and thus should be a better surrogate virus.…”

Section: Discussionmentioning

confidence: 99%

“…In most of the studies published so far, the MCV MC159 gene has been analyzed in cells overexpressing MC159 upon transient transfection with an expression plasmid. Only in a few studies has MC159 been expressed by a surrogate virus, a recombinant VACV with its caspase-8 inhibitor, B13R, deleted (10,13,18,48), and two other studies have examined MC159 functions in transgenic mice expressing the viral protein (19,49).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, M45 expressed transiently by plasmid transfection activates NF-B (33), whereas prolonged expression (e.g., by retroviral transduction) blocks NF-B activation (32). For MC159, it was also reported that it is able to both activate and inhibit NF-B (16)(17)(18)(19).…”

Section: Characterization Of MCMV Mc159 Substitution Mutantsmentioning

confidence: 99%

“…It has been shown that overexpression of MC159 inhibits NF-B activation by several stimuli, including death receptor stimulation or MyD88 overexpression (16)(17)(18), and that MC159 acts at the level of the inhibitor of B kinase (IKK) complex by interacting with the IKK␥ subunit (also called NF-B essential modulator [NEMO]) (18). However, it has also been shown that MC159 can activate NF-B: transient expression of MC159 in human Jurkat or 293 cells led to a significantly increased NF-B activity, and the ambivalent effect appeared to depend on MC159 and RIP1 expression levels (19).…”

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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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Molluscum Contagiosum Virus: Biology and Immune Response

Santacroce,

Magrone

2024

Advances in Experimental Medicine and Biology

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Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection

Cited by 26 publications

References 58 publications

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

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

Molluscum Contagiosum Virus: Biology and Immune Response

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