Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia

Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry; Cobat, Aurélie; Tarantino, Nadine; Hazen, Melissa; Lidov, Hart G.W.; Hopkins, Gregory; Du, Likun; Belkadi, Aziz; Chrabieh, Maya; Itan, Yuval; Pïcard, Capucine; Fournet, Jean‐Christophe; Eibel, Hermann; Tsitsikov, Erdyni; Pai, Sung-Yun; Abel, Laurent; Al‐Herz, Waleed; Casanova, Jean‐Laurent; Israël, Alain; Notarangelo, Luigi D.

doi:10.1084/jem.20141130

Cited by 254 publications

(249 citation statements)

References 70 publications

(138 reference statements)

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…This is a report of a human disease caused by excessive linear ubiquitination. Conversely, patients with LUBAC deficiency have impaired linear ubiquitination of the same target molecules, which leads to immunodeficiency due to decreased NF-κB activity in fibroblasts, and a concomitant inflammatory phenotype due to hyperresponsiveness to IL-1β in monocytes (4). These latter studies demonstrate cell type-specific functions of the LUBAC subunits HOIP and HOIL-1.…”

Section: Discussionmentioning

confidence: 92%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 92%

mentioning

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

View full text Add to dashboard Cite

show abstract

“…Fibroblast and lymphocytes isolated from these patients show diminished NF-kB activation, and monocytes have enhanced sensitivity to IL-1b stimulation, similar to that which has been described in experimental models. When subjected to allogenic engraftment of myeloid and lymphoid compartments, one patient was protected from pyogenic infection and systemic inflammation (65). The complex syndromes exhibited by these patients highlight the cell type-specific function of linear ubiquitination, which may contribute to this unique presentation of symptoms.…”

Section: Lubac Components and Diseasementioning

confidence: 99%

“…Autoinflammation in patients with LUBAC deficiency is characterized by recurrent fever with hepatosplenomegaly and lymphadenopathy at an early age, yet these patients do not develop additional hallmarks such as pleuritis, pericarditis, peritonitis, or neutrophilic dermatoses (65). These patients are prone to recurrent pyogenic infections and an abnormal antiviral host response.…”

Section: Lubac Components and Diseasementioning

confidence: 99%

Role of Linear Ubiquitination in Health and Disease

Brazee

Dada

Sznajder

2016

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

The covalent attachment of ubiquitin to target proteins is one of the most prevalent post-translational modifications, regulating a myriad of cellular processes including cell growth, survival, and metabolism. Recently, a novel RING E3 ligase complex was described, called linear ubiquitin assembly complex (LUBAC), which is capable of connecting ubiquitin molecules in a novel head-to-tail fashion via the N-terminal methionine residue. LUBAC is a heteromeric complex composed of heme-oxidized iron-responsive element-binding protein 2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein, and shankassociated RH domain-interacting protein (SHARPIN). The essential role of LUBAC-generated linear chains for activation of nuclear factorkB (NF-kB) signaling was first described in the activation of tumor necrosis factor-a receptor signaling complex. A decade of research has identified additional pathways that use LUBAC for downstream signaling, including CD40 ligand and the IL-1b receptor, as well as cytosolic pattern recognition receptors including nucleotide-binding oligomerization domain containing 2 (NOD2), retinoic acid-inducible gene 1 (RIG-1), and the NOD-like receptor family, pyrin domain containing 3 inflammasome (NLRP3). Even though the three components of the complex are required for full activation of NF-kB, the individual components of LUBAC regulate specific cell type-and stimuli-dependent effects. In humans, autosomal defects in LUBAC are associated with both autoinflammation and immunodeficiency, with additional disorders described in mice. Moreover, in the lung epithelium, HOIL-1L ubiquitinates target proteins independently of the other LUBAC components, adding another layer of complexity to the function and regulation of LUBAC. Although many advances have been made, the diverse functions of linear ubiquitin chains and the regulation of LUBAC are not yet completely understood. In this review, we discuss the various roles of linear ubiquitin chains and point to areas of study that would benefit from further investigation into LUBACmediated signaling pathways in lung pathophysiology.

show abstract

“…OTULIN binds to the PUB domain of HOIP and loss of HOIP-OTULIN interaction reduces OTULIN’s capacity to restrict LUBAC-induced immune responses [24]. LUBAC-deficient patients have susceptibility to bacterial infections along with episodes of pathogen-free systemic inflammation [25,26]. Mutant cells exhibited impaired NF-κB signaling in fibroblasts and B-cells and enhanced responses to IL-1 stimulation in monocytes, which likely accounts for the features of immunodeficiency and inflammation in these patients.…”

Section: Introductionmentioning

confidence: 99%

Lessons from characterization and treatment of the autoinflammatory syndromes

Aksentijevich

McDermott

2017

Current Opinion in Rheumatology

View full text Add to dashboard Cite

Purpose of review The list of genes associated with systemic inflammatory diseases has been steadily growing due to the explosion of new genomic technologies. Significant advances in the past year have deepened our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: Haploinsufficiency of A20 (HA20), otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis (sJIA). Recent findings The scope of autoinflammation has been broadened to include defects in deubiquitination and cellular redox homeostasis. At the clinical level we discuss the biological rationale for treatment with cytokine inhibitors and colchicine in respective conditions and the use of IL-1 antagonism for diagnostic and therapeutic purposes in the management of undifferentiated autoinflammatory disorders. Summary Gene discoveries coupled with studies of molecular function provide knowledge into the biology of inflammatory responses and form the basis for genomically-informed therapies. Diseases of dysregulated ubiquitination constitute a novel category of human inflammatory disorders.

show abstract

Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia

Cited by 254 publications

References 70 publications

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

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

Role of Linear Ubiquitination in Health and Disease

Lessons from characterization and treatment of the autoinflammatory syndromes

Contact Info

Product

Resources

About