Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

Boisson, Bertrand; Laplantine, Emmanuel; Prando, Carolina; Giliani, Silvia; Israelsson, Elisabeth; Xu, Zhaohui; Abhyankar, Avinash; Israël, Laura; Trevejo-Nuñez, Giraldina; Bogunovic, Dusan; Cepika, Alma-Martina; MacDuff, Donna A.; Chrabieh, Maya; Hubeau, Marjorie; Bajolle, Fanny; Debré, Marianne; Mazzolari, Evelina; Vairo, Donatella; Agou, Fabrice; Virgin, Herbert W.; Bossuyt, Xavier; Rambaud, Caroline; Facchetti, Fabio; Bonnet, Damien; Quartier, Pierre; Fournet, Jean‐Christophe; Pascual, Virginia; Chaussabel, Damien; Notarangelo, Luigi D.; Puel, Anne; Israël, Alain; Casanova, Jean‐Laurent; Pïcard, Capucine

doi:10.1038/ni.2457

Cited by 427 publications

(484 citation statements)

References 46 publications

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“…LUBAC regulates TNFα signaling by targeting the regulatory protein, NF-κB essential modulator (NEMO), for nondegradative linear ubiquitination. Depletion of LUBAC components by RNA interference or genetic ablation attenuates cytokine-driven NF-κB signaling [1][2][3][4][5]7].…”

Section: Dear Editormentioning

confidence: 99%

The ubiquitin conjugating enzyme UBE2L3 regulates TNFα-induced linear ubiquitination

Wang

et al. 2013

Cell Res

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Section: Dear Editormentioning

confidence: 99%

The ubiquitin conjugating enzyme UBE2L3 regulates TNFα-induced linear ubiquitination

Wang

et al. 2013

Cell Res

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“…Linear ubiquitin chains, also known as Met1-linked chains, are generated by the linear ubiquitin assembly complex (LUBAC) (2). LUBAC-mediated Met1 ubiquitination is critical for regulation of immune signaling and cell death (3). Absence of LUBAC attenuates NF-κB signaling and patients with loss-offunction mutations in LUBAC present with paradoxical features of susceptibility to infection and systemic inflammation, the latter due to increased responsiveness to IL-1β in monocytes (3)(4)(5).…”

mentioning

confidence: 99%

“…LUBAC-mediated Met1 ubiquitination is critical for regulation of immune signaling and cell death (3). Absence of LUBAC attenuates NF-κB signaling and patients with loss-offunction mutations in LUBAC present with paradoxical features of susceptibility to infection and systemic inflammation, the latter due to increased responsiveness to IL-1β in monocytes (3)(4)(5). OTULIN and CYLD are deubiquitinases (DUBs) that cleave Met1-linked chains (6).…”

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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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“…In cells isolated from cpdm mice, the amount of the other components of LUBAC, HOIL-1L and HOIP, was reduced drastically by the lack of SHARPIN, thereby attenuating canonical NF-κB activation induced by several stimuli including TNF-α and CD40 [ 13 -15 ]. Recently, loss-of-function mutation of HOIL-1L provoked a fatal human inherited disorder characterized by chronic autoinfl ammation, invasive bacterial infections, and muscular amylopectinosis [ 16 ]. Loss of HOIL-1L or SHARPIN destabilizes the other two components of LUBAC and thereby suppresses signalinduced NF-κB activation [ 5 , 13 -15 ].…”

Section: The Linear Ubiquitin Chains and Their Roles In Nf-κb Activationmentioning

confidence: 99%

Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

Iwaï

2015

Innovative Medicine

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NF-κB is a transcription factor known to be involved in pleomorphic biological phenomena such as infl ammation and immune responses. Abnormal activation of NF-κB has been reported in many pathological conditions, including malignant tumors. Therefore, the NF-κB activation pathway has been extensively studied and involvement of the ubiquitin conjugation system in the NF-κB activation pathways has been revealed. Although the ubiquitin conjugation system was discovered as a part of a protein degradation pathway, non-degradable roles of the ubiquitin system have been revealed recently. Several types of polyubiquitin chains exist in cells and the type of chain seems to determine how ubiquitinated proteins are regulated. We have identifi ed that a new type of polyubiquitin chain, the linear polyubiquitin chain, plays a crucial role in regulating the NF-κB activation pathway in non-degradable manner. In this chapter, the discovery, roles in NF-κB activation, and involvement in the pathogenesis of cancers of linear ubiquitination will be discussed. Keywords NF-κB • Ubiquitin • LUBAC • Linear ubiquitin chain • cpdm • B cell lymphoma The Ubiquitin Conjugation SystemThe ubiquitin system, which is one of the most extensively studied post-translational protein modifi cation systems, has been identifi ed as part of an energy-dependent degradation system [ 1 ]. Ubiquitin is a protein-based modifi er composed of 76 amino acids. Through the function of three enzymes called the ubiquitin-activating enzyme (E1), the ubiquitin conjugating enzyme (E2) and the ubiquitin ligase (E3), ubiquitin is conjugated to the substrate proteins that are recognized by E3s. Ubiquitin is added onto ubiquitin pre-conjugated to the substrates to generate polyubiquitin chains-polymer of ubiquitin. The proteasome recognizes the polyubiquitin chains

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Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

Cited by 427 publications

References 46 publications

The ubiquitin conjugating enzyme UBE2L3 regulates TNFα-induced linear ubiquitination

The ubiquitin conjugating enzyme UBE2L3 regulates TNFα-induced linear ubiquitination

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

Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

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