Caspase-8-mediated Cleavage Inhibits IRF-3 Protein by Facilitating Its Proteasome-mediated Degradation

Sears, Nathaniel C.; Sen, Ganes C.; Stark, George R.; Chattopadhyay, Saurabh

doi:10.1074/jbc.m111.257022

Cited by 38 publications

(39 citation statements)

References 40 publications

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“…For certain substrates removal of a regulatory domain results in their constitutive activation, as in the case of various kinases (11,12). For others, cleavage results in a loss of function, and the resulting fragments are frequently degraded by the 26S proteasome (5)(6)(7)(8)(9)(10). In this study, we found an interaction between caspases and the ubiquitin-proteasome system.…”

Section: Discussionmentioning

confidence: 53%

“…Caspase cleavage can inactivate proteins or generate dominant-negative inhibitors, as in the case of gelsolin, RIP1, and eIF4E-BP1 (4). Moreover, caspase cleavage of numerous substrates, including IRF-3, ErbB2, cyclin E, claspin, SSRP1, and Twist, can enhance their turnover by the proteasome (5)(6)(7)(8)(9)(10). Conversely, caspases can also constitutively activate proteins, particularly kinases such as PKC and Mst1 (11,12), or change the function of a protein altogether, as seen in the conversion of antiapoptotic BCL-2 proteins into proapoptotic BAX-like proteins (13).…”

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confidence: 99%

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Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Yeh¹,

Bratton²

2013

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

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Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lysine necessary for ubiquitinylation as well as any existing ubiquitin conjugates. Cleavage therefore enhances the stability of Grim and initiates a feed-forward caspase amplification loop, resulting in greater cell death. In summary, Grim is a caspase substrate whose cleavage promotes apoptosis by limiting, in a target-specific fashion, its ubiquitinylation and turnover by the proteasome.

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Yeh¹,

Bratton²

2013

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

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“…MC160 is known to interact with procaspase-8 (39). It was published recently that procapase-8 cleaves IRF3 to induce IRF3 degradation as a means to down-regulate expression of genes induced by IRF3 (62). However, the IRF3 protein is neither decreased nor cleaved in MC160-expressing cells under conditions in which IRF3 is inactive or triggered (S1), suggesting that MC160 did not directly or indirectly target the IRF3 protein as its mechanism of inhibition.…”

Section: Resultsmentioning

confidence: 91%

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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“…Caspase Activity Is Required for Vpu-induced IRF3 Cleavage-It was previously reported that infection with Sendai virus or adenovirus caused cleavage of IRF3 by caspase-8 (28). To examine whether Vpu-induced IRF3 cleavage is dependent on caspase activity, 293T cells co-expressing IRF3 and Vpu were incubated for 8 h with the pan-caspase inhibitor Z-VAD or with the lysosomal acidification inhibitor bafilomycin A1 (BFM), MG132, or vehicle (DMSO) as controls.…”

Section: Resultsmentioning

confidence: 99%

“…However, there is precedent for viruses exploiting caspase activation to evade host immune responses (39). We have already mentioned the induction of caspase-mediated cleavage of IRF3 by infection with Sendai virus and adenovirus (28). In addition, poliovirus infection promotes caspase-mediated cleavage of the cytoplasmic RNA helicase MDA-5, which senses the viral doublestranded RNA in the context of the innate anti-viral response (40).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

Park

Waheed

Zhang

et al. 2014

Journal of Biological Chemistry

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Background:The transcription factor IRF3 is not properly activated during HIV-1 infection. Results: Infection with VSV-G-pseudotyped HIV-1 induces caspase-mediated cleavage of IRF3, and Vpu contributes to this event. Conclusion:The product of IRF3 cleavage by HIV-1 interferes with IRF3-regulated gene expression. Significance: Our findings contribute to the understanding of how HIV-1 attenuates the innate anti-viral response.

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Caspase-8-mediated Cleavage Inhibits IRF-3 Protein by Facilitating Its Proteasome-mediated Degradation

Cited by 38 publications

References 40 publications

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

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

HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

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