OTULIN deficiency causes auto-inflammatory syndrome

Fiil, Berthe Katrine; Gyrd‐Hansen, Mads

doi:10.1038/cr.2016.113

Cited by 13 publications

(15 citation statements)

References 12 publications

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“…Although little is known about FAM105A function, GWAS of allergic diseases implicates a credible missense risk variant in this gene (Ferreira et al, 2017). A neighboring paralogue gene, Otulin ( FAM105B ), encodes a deubiquitinase with an essential role in immune regulation (Damgaard et al, 2016; Fiil and Gyrd-Hansen, 2016) (Figure S6D). These results suggest an important role for FAM105A in mediating adenosine immunosuppressive signals in T cells.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

Shifrut

Carnevale

Tobin

et al. 2018

Cell

385

354

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SUMMARY Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, sgRNA lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells. Genome-wide loss-of-function screens identified essential T cell receptor signaling components and genes that negatively tune proliferation following stimulation. Targeted ablation of individual candidate genes characterized hits and identified perturbations that enhanced cancer cell killing. SLICE coupled with single-cell RNA-Seq revealed signature stimulation-response gene programs altered by key genetic perturbations. SLICE genome-wide screening was also adaptable to identify mediators of immunosuppression, revealing genes controlling responses to adenosine signaling. The SLICE platform enables unbiased discovery and characterization of functional gene targets in primary cells.

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Section: Resultsmentioning

confidence: 99%

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

Shifrut

Carnevale

Tobin

et al. 2018

Cell

385

354

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“…OTULIN specifically binds to Met l-Ub and LUBAC and hydrolyzes the Met l-Ub chain bound to the substrate specifically (not acting on the nonubiquitinated protein), allowing ubiquitination and deubiquitination of the substrate to maintain homeostasis for participation in a variety of biological functions in the organism. Research has shown that homozygous mutations in the human OTULIN gene can lead to potentially lethal autoinflammatory states, known as OTULIN-related autoimmune syndrome (ORAS) (43).…”

Section: Discussionmentioning

confidence: 99%

The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

Shi

Zhang

et al. 2018

J Virol

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Linear ubiquitination plays an important role in the regulation of the immune response by regulating nuclear factor κB (NF-κB). The linear ubiquitination-specific deubiquitinase ovarian tumor domain deubiquitinase with linear linkage specificity (OTULIN) can control the immune signaling transduction pathway by restricting the Met1-linked ubiquitination process. In our study, the porcine OTLLIN gene was cloned and deubiquitin functions were detected in a porcine reproductive and respiratory syndrome virus (PRRSV)-infected-cell model. PRRSV infection promotes the expression of the OTULIN gene; in turn, overexpression of OTULIN contributes to PRRSV proliferation. There is negative regulation of innate immunity with OTULIN during viral infection. The cooperative effects of swine OTULIN and PRRSV Nsp11 potentiate the ability to reduce levels of cellular protein ubiquitin associated with innate immunity. Importantly, PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to enhance its ability to remove linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I interferons (IFNs). Our report presents a new model of virus utilization of the ubiquitin-protease system from the perspective of the viral proteins that interact with cell deubiquitination enzymes, providing new ideas for prevention and control of PRRSV. Deubiquitination effects of swine OTULIN were identified. The interaction between porcine OTULIN and PRRSV Nsp11 is dependent on the OTU domain. PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to promote removal of linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I IFNs.

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“…OTULIN is a DUB that structurally solely constitutes the OTU domain with an N-terminal PUB-interacting motif, which is selective for binding methionine1-linked Ub chains in NF-κB transmitters [ 143 , 147 ]. Its systematic deficiency in expression causes OTULIN-related autoinflammatory syndrome (ORAS), which results in steatosis-alike liver inflammation [ 148 ]. However, not much is known about OTULIN and ORAS, as this protein functionality is still poorly understood and requires further investigations.…”

Section: Nf-κb-regulating Molecular Factorsmentioning

confidence: 99%

The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

Nowak

Relja

2020

IJMS

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Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

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OTULIN deficiency causes auto-inflammatory syndrome

Cited by 13 publications

References 12 publications

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

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