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

Zhou, Qing; Yu, Xiaomin; Demirkaya, Erkan; Deuitch, Natalie; Stone, Deborah L.; Tsai, Wanxia Li; Kuehn, Hye Sun; Wang, Hongying; Yang, Dan; Park, Yong Hwan; Ombrello, Amanda K.; Blake, Mary; Romeo, Tina; Remmers, Elaine F.; Chae, Jae Jin; Mullikin, James C.; Güzel, Ferhat; Milner, Joshua D.; Boehm, Manfred; Rosenzweig, Sergio D.; Gadina, Massimo; Welch, S; Özen, Seza; Topaloğlu, Rezan; Abinun, Mario; Kastner, Daniel L.; Aksentijevich, Ivona

doi:10.1073/pnas.1612594113

Cited by 232 publications

(315 citation statements)

References 20 publications

(28 reference statements)

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“…Two out of three patients respond to anti-TNF treatment with the third patient being treated with anti-IL-1β (anakinra) and steroids. The analysis of patient samples show, in agreement with Damgaard et al, increased levels of Met1-Ub and increased cytokine production relative to cells from healthy donors [10].…”

supporting

confidence: 88%

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OTULIN deficiency causes auto-inflammatory syndrome

Fiil

Gyrd‐Hansen

2016

Cell Res

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Ubiquitin chains assembled via the N-terminal methionine (Met1 or linear ubiquitin), conjugated by the linear ubiquitin chain assembly complex (LUBAC), participate in NF-κΒ-dependent inflammatory signaling and immune responses. A recent report in Cell finds that OTU-LIN, a deubiquitinase that selectively cleaves Met1-linked ubiquitin chains, is essential for restraining inflammation in vivo.Ubiquitin signaling controls activation of nuclear factor-κB (NF-κB) and inflammatory responses upon engagement of pattern recognition receptors and cytokine receptors such as tumor necrosis factor (TNF) receptor 1 (TNFR1). Ubiquitin chains linked via lysine 63 (Lys63-Ub) and methionine 1 (Met1-Ub) are formed on protein substrates after receptor activation and coordinate activation of downstream kinase complexes, leading to NF-κB-dependent transcription [1]. Met1-Ub chains are assembled by the linear ubiquitin chain assembly complex (LU-BAC), composed of HOIP, HOIL-1, and SHARPIN [1]. LUBAC function is regulated by the deubiquitinases (DUBs) OTULIN [2-4] and CYLD [5][6][7], which both associate with the catalytic subunit HOIP [5][6][7][8].Previous studies have revealed that OTULIN exclusively hydrolyzes Met1-Ub, prevents accumulation of Met1-Ub on LUBAC components under basal conditions, and restricts ubiquitination of LUBAC substrates after receptor stimulation [2][3][4]. However, the contribution of OTULIN to regulation of physiological immune responses had not been investigated.

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supporting

confidence: 88%

“…A separate recent study also identified patients with mutations in OTULIN [10]. In addition to the L272P mutation, the study identifies two other mutations in the OTU domain.…”

mentioning

confidence: 90%

OTULIN deficiency causes auto-inflammatory syndrome

Fiil

Gyrd‐Hansen

2016

Cell Res

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“…To determine the mechanism by which RNF31 regulates NF-B activation and cell death, further investigations are required. Additionally, the deubiquitinase enzyme OTULIN has been reported to play an essential role in NF-B signaling pathways and inflammation by deconjugating linear ubiquitination from substrates (21,22), and recently, clinical evidence from ORAS (OTULIN-related autoinflammatory syndrome) patients supported the fundamental role of OTULIN in human disease (19,23). Since OTULIN binds with the PUB domain of RNF31 (located in the RNF31 NT mutant), further investigation on the regulation of OTULIN function by RNF31 cleavage will elucidate the mechanism of linear ubiquitinationmediated signaling and its biological significance.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31

Joo

Tang

Blonska

et al. 2016

Molecular and Cellular Biology

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Cell death and survival signaling pathways have opposed but fundamental functions for various cellular processes and maintain cell homeostasis through cross talk. Here we report a novel mechanism of interaction between these two pathways through the cleavage of RNF31 by caspases. RNF31, a component of the linear ubiquitin chain assembly complex (LUBAC), regulates cell survival by inducing linear ubiquitination of NF-B signaling components. We found that RNF31 is cleaved under apoptosis conditions through various stimulations. The effector caspases caspase 3 and caspase 6 are responsible for this event, and aspartates 348, 387, and 390 were identified as target sites for this cleavage. Cleavage of RNF31 suppressed its ability to activate NF-B signaling; thus, mutation of cleavage sites inhibited the induction of apoptosis by treatment with tumor necrosis factor alpha (TNF-␣). Our findings elucidate a novel regulatory loop between cell death and the survival signal and may provide guidance for the development of therapeutic strategies for cancers through the sensitization of tumor cells to death-inducing drugs. The nuclear factor B (NF-B) signaling pathway plays a critical role in various cellular processes, including proliferation, differentiation, survival, and death. In the resting state, inhibitor of B-␣ (IB-␣) sequesters the NF-B complex in the cytoplasm by interacting with it. Through the activation of the IB kinase (IKK) complex (composed of IKK␣, -␤, and -␥), followed by the phosphorylation and consequent degradation of IB-␣, free NF-B complex acquires the ability to enter the nucleus and induce target gene expression (1). Previous studies have revealed that K63-linked polyubiquitination of IKK␥ (also called NEMO) is critical for NF-B activation (2). Recently, linear ubiquitination was identified as a novel type of ubiquitination that forms the ubiquitin linkage between the N-terminal Met of one ubiquitin and the C-terminal Gly of another (3-5). To date, the linear ubiquitin chain assembly complex (LUBAC), which is composed of one main E3 ligase, ring finger protein 31 (RNF31; also known as HOIP), and two associated proteins, HOIL-1 and Sharpin, is the only E3 ligase complex for linear ubiquitination. Upstream activation leads to the linear ubiquitination of NEMO. Then these modified molecules function as a bridge between the receptor complex and the downstream IKK complex to activate NF-B signaling (6). Genetic studies have shown that defects in HOIL-1 or Sharpin result in reduced phosphorylation and degradation of IB-␣, impaired and delayed nuclear translocation of the NF-B subunit p65, diminished overall gene induction, and increased tumor necrosis factor (TNF)-induced cell death (3-5).The activation of NF-B signaling not only directly prompts cell growth and proliferation but also suppresses cell death by upregulating antiapoptotic molecules that inhibit the function of caspases. Caspases are regulatory proteases that are essential for apoptosis activation. Briefly, diverse factors, including TNF-␣, TN...

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“…Data analysis was performed as described previously, 20 with slight modifications. Considering the low explained heritability of PM, we thus expect the variants to be rare in population samples.…”

Section: Mutation Screeningmentioning

confidence: 99%

A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia

Wang

Liu

Chen

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Pathologic myopia described as myopia accompanied by severe deformation of the eye besides excessive elongation of eye, is usually a genetic heterogeneous disorder characterized by extreme, familial, early-onset vision loss. However, the exact pathogenesis of pathologic myopia remains unclear. In this study, we screened a Han Chinese family with pathologic myopia to identify the causative mutation and explore the possible pathogenic mechanism based on evaluation of the biological functions of the mutation. METHODS.We identified the mutations in a family with pathologic myopia by single nucleotide polymorphism array combined with short tandem repeat microsatellite marker analysis and exome sequencing. Mutations were validated among family members by direct Sanger sequencing. The subcellular localization of the protein variant was investigated by immunofluorescence, and the stability of the mutant protein was determined by immunoblotting. Intracellular levels of adenosine triphosphate and reactive oxygen species and complex I activity were measured by traditional biochemical methods to determine the functional role of the disease-associated mutation.RESULTS. The novel missense mutation: c.798C>G (p.Asp266Glu) in NDUFAF7, cosegregated with the disease and the resulting amino acid substitution affected a highly conserved residue in its protein. The mutation D266E in NDUFAF7 impaired complex I activity, which resulted in decreased ATP levels in cultured cells. CONCLUSIONS.We propose that the heterozygous mutation (c.798C>G) in NDUFAF7 may contribute to the pathogenesis of pathologic myopia, possibly by interfering with the phototransduction cascade. Mitochondrial dysfunction during eye development may lead to pathologic myopia.Keywords: pathologic myopia, NDUFAF7, causative mutation H igh myopia is an extreme form of myopia, usually defined by an ocular axial length >26 mm or a refractive error < À6.00 diopters (D). High myopia is a leading cause of blindness worldwide, with a relatively high prevalence of 1% to 5% in Asian countries, and as high as 4.1% in China. [1][2][3][4] High myopia can be complicated by pathology in 8% of high myopia in that there might be other genetic variants that play a role in this process compared to high myopia without pathology.5-8 Pathologic myopia (PM) generally causes irreversible visual impairment, which involves not only elongation of the eye, but also characteristic pathologic changes in the retina, choroid, and sclera, such as posterior sclera staphyloma, macular degeneration, lacquer cracks, and chorioretinal atrophy.9 Pathologic myopia is highly heritable, and genetic linkage studies have identified over 20 loci for PM, with autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. [10][11][12][13] More than 70 genes related to refractive variation have been screened out by association studies. 14 Furthermore, recent studies have indicated that environment is another factor influencing the growth of the eye.15 Environmental factors, such as ...

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

Cited by 232 publications

References 20 publications

OTULIN deficiency causes auto-inflammatory syndrome

OTULIN deficiency causes auto-inflammatory syndrome

Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31

A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia

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