Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling

Emmerich, Christoph H.; Bakshi, Siddharth; Kelsall, Ian R.; Ortiz-Guerrero, Juanma; Shpiro, Natalia; Cohen, Philip

doi:10.1016/j.bbrc.2016.04.141

Cited by 82 publications

(84 citation statements)

References 43 publications

(63 reference statements)

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“…By contrast, the analysis of heterotypic chain types has relied entirely on indirect means, such as in vitro reconstitution, treatment of purified chains with deubiquitylases, or expression of engineered ubiquitin variants. Such experiments suggested that M1/K63-linked chains control NFκB transcription factor activation (Emmerich et al, 2016; Emmerich et al, 2013; Wertz et al, 2015), while K11/K48-branched chains signal the degradation of cell cycle regulators during mitosis (Meyer and Rape, 2014). Similar in vitro or protein engineering evidence exists for K48/K63-branched, K29/K48-linked or more complex heterotypic chains (Kim et al, 2007; Koegl et al, 1999; Kristariyanto et al, 2015; Liu et al, 2017; Ohtake et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

Yau

Doerner

Castellanos³

et al. 2017

Cell

265

276

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Summary Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation- prone proteins. By revealing key roles of K11/K48-linked chains in cell cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.

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Section: Introductionmentioning

confidence: 99%

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

Yau

Doerner

Castellanos³

et al. 2017

Cell

265

276

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“…TNF also stimulates the formation of M1-linked and K63/M1-ubiquitin hybrid chains on NEMO (28,50). K63-linked chains are substrates for M1-linked polyubiquitination (28,50). Since MC159 inhibited K63-linked ubiquitination (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…For example, the K63-linked polyubiquitination of NEMO was the first type of ubiquitination event shown to be important for TNF-induced NF-B activation (23,24). TNF also stimulates the formation of M1-linked and K63/M1-ubiquitin hybrid chains on NEMO (28,50). K63-linked chains are substrates for M1-linked polyubiquitination (28,50).…”

Section: Discussionmentioning

confidence: 99%

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Molluscum Contagiosum Virus MC159 Abrogates cIAP1-NEMO Interactions and Inhibits NEMO Polyubiquitination

Biswas

Shisler

2017

J Virol

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Molluscum contagiosum virus (MCV) is a dermatotropic poxvirus that causes benign skin lesions. MCV lesions persist because of virally encoded immune evasion molecules that inhibit antiviral responses. The MCV MC159 protein suppresses NF-B activation, a powerful antiviral response, via interactions with the NF-B essential modulator (NEMO) subunit of the IB kinase (IKK) complex. Binding of MC159 to NEMO does not disrupt the IKK complex, implying that MC159 prevents IKK activation via an as-yet-unidentified strategy. Here, we demonstrated that MC159 inhibited NEMO polyubiquitination, a posttranslational modification required for IKK and downstream NF-B activation. Because MCV cannot be propagated in cell culture, MC159 was expressed independent of infection or during a surrogate vaccinia virus infection to identify how MC159 prevented polyubiquitination. Cellular inhibitor of apoptosis protein 1 (cIAP1) is a cellular E3 ligase that ubiquitinates NEMO. Mutational analyses revealed that MC159 and cIAP1 each bind to the same NEMO region, suggesting that MC159 may competitively inhibit cIAP1-NEMO interactions. Indeed, MC159 prevented cIAP1-NEMO interactions. MC159 also diminished cIAP1-mediated NEMO polyubiquitination and cIAP1-induced NF-B activation. These data suggest that MC159 competitively binds to NEMO to prevent cIAP1-induced NEMO polyubiquitination. To our knowledge, this is the first report of a viral protein disrupting NEMO-cIAP1 interactions to strategically suppress IKK activation. All viruses must antagonize antiviral signaling events for survival. We hypothesize that MC159 inhibits NEMO polyubiquitination as a clever strategy to manipulate the host cell environment to the benefit of the virus. IMPORTANCE Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes persistent skin neoplasms. The persistence of MCV has been attributed to viral downregulation of host cell immune responses such as NF-B activation. We show here that the MCV MC159 protein interacts with the NEMO subunit of the IKK complex to prevent NEMO interactions with the cIAP1 E3 ubiquitin ligase. This interaction correlates with a dampening of cIAP1 to polyubiquitinate NEMO and to activate NF-B. This inhibition of cIAP1-NEMO interactions is a new viral strategy to minimize IKK activation and to control NEMO polyubiquitination. This research provides new insights into mechanisms that persistent viruses may use to cause long-term infection of host cells.

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“…Additionally, the roles of branched Lys63/Met1 chains are emerging in other inflammatory signalling pathways such as the NOD2 receptor complex [42,144], suggesting that this could be a unifying mechanism for the TAK1-dependent activation of the IKK complex and explaining the differing and important roles of Lys63 and Met1 polyubiquitin linkages.…”

Section: Regulation Of the Met1 Machinerymentioning

confidence: 99%

Molecular basis for specificity of the Met1-linked polyubiquitin signal

Elliott

2016

Biochemical Society Transactions

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The post-translational modification of proteins provides a rapid and versatile system for regulating all signalling pathways. Protein ubiquitination is one such type of post-translational modification involved in controlling numerous cellular processes. The unique ability of ubiquitin to form polyubiquitin chains creates a highly complex code responsible for different subsequent signalling outcomes. Specialised enzymes (‘writers’) generate the ubiquitin code, whereas other enzymes (‘erasers’) disassemble it. Importantly, the ubiquitin code is deciphered by different ubiquitin-binding proteins (‘readers’) functioning to elicit particular cellular responses. Ten years ago, the methionine1 (Met1)-linked (linear) polyubiquitin code was first identified and the intervening years have witnessed a seismic shift in our understanding of Met1-linked polyubiquitin in cellular processes, particularly inflammatory signalling. This review will discuss the molecular mechanisms of specificity determination within Met1-linked polyubiquitin signalling.

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Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling

Cited by 82 publications

References 43 publications

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

Molluscum Contagiosum Virus MC159 Abrogates cIAP1-NEMO Interactions and Inhibits NEMO Polyubiquitination

Molecular basis for specificity of the Met1-linked polyubiquitin signal

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