The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation

Rodgers, Mary A.; Bowman, James W.; Fujita, Hiroaki; Orazio, Nicole I.; Shi, Mude; Liang, Qiming; Amatya, Rina; Kelly, Thomas J.; Iwaï, Kazuhiro; Ting, Jenny P.Y.; Jung, Jae U.

doi:10.1084/jem.20132486

Cited by 221 publications

(203 citation statements)

References 60 publications

(156 reference statements)

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“…This raises the possibility of specific host protein DAMPs that are homologous with bacterial NAIP ligands, or that certain DAMPs or tissue/cellular stresses activate posttranslational mechanisms, causing activation of NLRC4. Recent work from our group and others has identified ubiquitin posttranslational modification of NLRP3 inflammasome components as a key integrator of diverse DAMP signals (35)(36)(37)(38). Interestingly, ubiquitination has also been suggested to regulate the activation of NLRC4 in a model of caspase-8-dependent cell death (39).…”

Section: Discussionmentioning

confidence: 98%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

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

233

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Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated specklike protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.inflammation | inflammasome | cerebral ischemia | brain injury | cell death

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Section: Discussionmentioning

confidence: 98%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

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

233

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“…111 Recently, HOIL-1L, a component of linear ubiquitination assembly complex (LUBAC), was found to be an essential activator of NLRP3/ASC inflammasome assembly through linear ubiquitination of ASC, a novel LUBAC substrate. 112 Additionally, the direct binding of NLRP3 to the mitochondrial lipid cardiolipin is important for NLRP3 inflammasome activation in response to both ROSdependent and -independent activators. 73 Recent studies showed that DHX33, a member of the DExD/ H-box helicase family, plays a role in activation of the NLRP3 inflammasome through interaction with NLRP3.…”

Section: Adaptors/molecules Involved In Activation Of the Nlrp3 Inflamentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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“…S4 B and C). OTULIN cleaves Met1-linked linear polyubiquitin chains from target substrates, such as NEMO (IKKγ), RIPK1, ASC, and TNFR1 to restrict signaling activation and propagation (7,14,15). To investigate the effect of OTULIN mutations on its deubiquitinase function, we cotransfected WT and mutant OTULIN plasmids into HEK293 cells along with plasmids encoding the LUBAC subunits, mono specific-ubiquitin plasmid, and each of the OTULIN substrates NEMO (Fig.…”

Section: Significancementioning

confidence: 99%

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

Zhou

Demirkaya

et al. 2016

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

232

275

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Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.OTULIN | linear deubiquitinase | NF-κB pathway | autoinflammatory disease | cytokines

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The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation

Abstract: Independent of its known role in NF-κB transcription, the HOIL-1L containing LUBAC is required for assembly and activation of the NLRP3 inflammasome via linear ubiquitination of ASC.

Cited by 221 publications

References 60 publications

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Molecular mechanisms regulating NLRP3 inflammasome activation

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

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