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Responsible editorZyme auto-inflammatory disease refers to a type of immune disease that is mediated by innate immunity and clinically manifests as abnormally increased inflammation and recurrent systemic inflammation, such as DADA2 (ADA2 deficiency), HA20 (A20 single times less than the dose), CRIA syndrome
.
The main clinical manifestations include periodic fever, skin rash, lymphadenopathy, hepatosplenomegaly, arthritis, inflammatory bowel disease, vasculitis, basal ganglia calcification, pulmonary interstitial disease, blood system and immune system involvement, etc.
, as well as indicators of inflammation CRP and ESR increased
.
The discovery of new pathogenic genes for autoinflammatory diseases and the study of pathogenic mechanisms can improve the diagnosis of autoinflammatory diseases, expand the understanding of autoinflammatory diseases, and promote the treatment of patients with difficult autoinflammatory diseases.
Therefore, it is very important Meaning
.
Otulipenia (OTULIN defect) is an autosomal recessive genetic disease caused by OTULIN mutations, which was first reported and named by Researcher Zhou Qing and Researcher Yu Xiaomin in 2016 (PNAS, 2016)
.
The patient’s clinical manifestations include recurrent fever, skin nodules, lipodystrophy, panniculitis, hepatosplenomegaly, arthritis, and developmental delay
.
OTULIN is a linear ubiquitination-specific deubiquitinating enzyme, which is recruited into the cell necrosis factor receptor (TNFR1) complex through the linear ubiquitin chain assembly complex (LUBAC) to cleave some substrates such as NEMO and RIPK1 On the linear ubiquitin chain, and then negatively regulate the NF-κB signaling pathway
.
The NEMO and RIPK1 in peripheral blood mononuclear cells (PBMCs) of patients with OTULIN deficiency have excessive linear ubiquitin chain accumulation, which activates the NF-κB signaling pathway and leads to the release of pro-inflammatory cytokines (PNAS, 2016)
.
However, OTULIN does not only regulate the NF-κB signaling pathway.
In 2018, Vishva M.
Dixit's research group reported that the deficiency of OTULIN enzyme activity can lead to the activation of type I interferon (IFN-I) signaling pathway in mice
.
Recently, the team of Zhou Qing and Yu Xiaomin of Zhejiang University published a research paper entitled Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production in Science Advances
.
The study found that the IFN-I signaling pathway was over-activated in the cells of patients with OTULIN deficiency, and that the proteasome subunits can be used as substrates for OTULIN deubiquitination.
OTULIN deficiency can lead to defects in the assembly of the proteasome complex and reduced enzyme activity
.
Through transcriptomics analysis and cytokine protein level analysis, the authors found that in addition to the up-regulation of NF-κB signaling pathway in peripheral blood mononuclear cells, monocytes and serum of patients, activation of IFN-I signaling pathway also exists compared with healthy controls.
Significant increase
.
In order to further study the mechanism of OTULIN deficiency leading to excessive activation of the IFN-I signaling pathway, co-immunoprecipitation-mass spectrometry experiments revealed that multiple subunits of OTULIN and the proteasome complex have co-immunoprecipitation, which suggests that linear ubiquitination may be involved in proteases.
Body assembly or regulation of enzyme activity
.
Through experiments such as proteasome enzyme activity detection and non-denaturing electrophoresis, it has been found that the proteasome complexes in patient-derived fibroblasts and peripheral blood mononuclear cells have assembly defects and reduced enzyme activity, which in turn causes more K48 in the cells.
Accumulation of polyubiquitinated proteins
.
Studies have found that some proteasome subunits, including immune proteasome subunits, can be used as substrates of LUBAC complex and OTULIN, undergoing linear ubiquitination modification, and the accumulation of proteasome linear ubiquitin chains caused by OTULIN defects will affect its assembly and Enzyme activity
.
This study reported for the first time that OTULIN deficiency can lead to excessive activation of IFN-I inflammatory signaling pathways in patient cells, which provides theoretical guidance for the choice of JAK inhibitors in patient treatment options
.
At the same time, this study identified multiple proteasome subunits as substrates for OTULIN de-linear ubiquitination.
The linear ubiquitination modification of the proteasome was discovered for the first time, and OTULIN defects lead to defects in the proteasome assembly and enzyme activity in patient cells
.
Clinically, OTULIN deficiency is very similar to the clinical phenotype of CANDLE syndrome, another autoinflammatory disease
.
Mutations in genes encoding proteasome subunits, such as PSMB8, PSMB10, etc.
, can lead to CANDLE syndrome.
CANDLE syndrome is a type I interferon disease with excessive activation of the IFN signaling pathway
.
Similar to CANDLE patients, the defects of proteasome assembly and enzymatic activity in OTULIN-deficient cells cause disorders of intracellular ubiquitination-proteasome-related signaling pathways, which in turn leads to excessive activation and inflammation of type I interferon signaling pathways in patients Phenotype, therefore, explains the high degree of consistency of the clinical phenotypes of OTULIN deficiency and proteasome deficiency CANDLE syndrome from the mechanism, and provides new clues for studying the pathogenesis of autoinflammatory diseases
.
Researcher Zhou Qing from Zhejiang University Institute of Life Sciences and researcher Yu Xiaomin from Zhejiang University Medical Center/Liangzhu Laboratory are the corresponding authors of this article
.
Dr.
Tao Panfeng and Dr.
Wang Shihao from Zhejiang University are the co-first authors of this article .
Original link: https:// Platemaker: 11 References 1.
Qing Zhou*, Xiaomin Yu*, Erkan Demirkaya, et al.
Biallelic hypomorphic mutations in a linear deubiquitinase define Otulipenia, an early-onset autoinflammatory disease.
Proceedings of the National Academy of Sciences, 2016 Sep 6;113(36):10127-32.
Reprint Instructions [Non-original articles] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated
.
.
The main clinical manifestations include periodic fever, skin rash, lymphadenopathy, hepatosplenomegaly, arthritis, inflammatory bowel disease, vasculitis, basal ganglia calcification, pulmonary interstitial disease, blood system and immune system involvement, etc.
, as well as indicators of inflammation CRP and ESR increased
.
The discovery of new pathogenic genes for autoinflammatory diseases and the study of pathogenic mechanisms can improve the diagnosis of autoinflammatory diseases, expand the understanding of autoinflammatory diseases, and promote the treatment of patients with difficult autoinflammatory diseases.
Therefore, it is very important Meaning
.
Otulipenia (OTULIN defect) is an autosomal recessive genetic disease caused by OTULIN mutations, which was first reported and named by Researcher Zhou Qing and Researcher Yu Xiaomin in 2016 (PNAS, 2016)
.
The patient’s clinical manifestations include recurrent fever, skin nodules, lipodystrophy, panniculitis, hepatosplenomegaly, arthritis, and developmental delay
.
OTULIN is a linear ubiquitination-specific deubiquitinating enzyme, which is recruited into the cell necrosis factor receptor (TNFR1) complex through the linear ubiquitin chain assembly complex (LUBAC) to cleave some substrates such as NEMO and RIPK1 On the linear ubiquitin chain, and then negatively regulate the NF-κB signaling pathway
.
The NEMO and RIPK1 in peripheral blood mononuclear cells (PBMCs) of patients with OTULIN deficiency have excessive linear ubiquitin chain accumulation, which activates the NF-κB signaling pathway and leads to the release of pro-inflammatory cytokines (PNAS, 2016)
.
However, OTULIN does not only regulate the NF-κB signaling pathway.
In 2018, Vishva M.
Dixit's research group reported that the deficiency of OTULIN enzyme activity can lead to the activation of type I interferon (IFN-I) signaling pathway in mice
.
Recently, the team of Zhou Qing and Yu Xiaomin of Zhejiang University published a research paper entitled Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production in Science Advances
.
The study found that the IFN-I signaling pathway was over-activated in the cells of patients with OTULIN deficiency, and that the proteasome subunits can be used as substrates for OTULIN deubiquitination.
OTULIN deficiency can lead to defects in the assembly of the proteasome complex and reduced enzyme activity
.
Through transcriptomics analysis and cytokine protein level analysis, the authors found that in addition to the up-regulation of NF-κB signaling pathway in peripheral blood mononuclear cells, monocytes and serum of patients, activation of IFN-I signaling pathway also exists compared with healthy controls.
Significant increase
.
In order to further study the mechanism of OTULIN deficiency leading to excessive activation of the IFN-I signaling pathway, co-immunoprecipitation-mass spectrometry experiments revealed that multiple subunits of OTULIN and the proteasome complex have co-immunoprecipitation, which suggests that linear ubiquitination may be involved in proteases.
Body assembly or regulation of enzyme activity
.
Through experiments such as proteasome enzyme activity detection and non-denaturing electrophoresis, it has been found that the proteasome complexes in patient-derived fibroblasts and peripheral blood mononuclear cells have assembly defects and reduced enzyme activity, which in turn causes more K48 in the cells.
Accumulation of polyubiquitinated proteins
.
Studies have found that some proteasome subunits, including immune proteasome subunits, can be used as substrates of LUBAC complex and OTULIN, undergoing linear ubiquitination modification, and the accumulation of proteasome linear ubiquitin chains caused by OTULIN defects will affect its assembly and Enzyme activity
.
This study reported for the first time that OTULIN deficiency can lead to excessive activation of IFN-I inflammatory signaling pathways in patient cells, which provides theoretical guidance for the choice of JAK inhibitors in patient treatment options
.
At the same time, this study identified multiple proteasome subunits as substrates for OTULIN de-linear ubiquitination.
The linear ubiquitination modification of the proteasome was discovered for the first time, and OTULIN defects lead to defects in the proteasome assembly and enzyme activity in patient cells
.
Clinically, OTULIN deficiency is very similar to the clinical phenotype of CANDLE syndrome, another autoinflammatory disease
.
Mutations in genes encoding proteasome subunits, such as PSMB8, PSMB10, etc.
, can lead to CANDLE syndrome.
CANDLE syndrome is a type I interferon disease with excessive activation of the IFN signaling pathway
.
Similar to CANDLE patients, the defects of proteasome assembly and enzymatic activity in OTULIN-deficient cells cause disorders of intracellular ubiquitination-proteasome-related signaling pathways, which in turn leads to excessive activation and inflammation of type I interferon signaling pathways in patients Phenotype, therefore, explains the high degree of consistency of the clinical phenotypes of OTULIN deficiency and proteasome deficiency CANDLE syndrome from the mechanism, and provides new clues for studying the pathogenesis of autoinflammatory diseases
.
Researcher Zhou Qing from Zhejiang University Institute of Life Sciences and researcher Yu Xiaomin from Zhejiang University Medical Center/Liangzhu Laboratory are the corresponding authors of this article
.
Dr.
Tao Panfeng and Dr.
Wang Shihao from Zhejiang University are the co-first authors of this article .
Original link: https:// Platemaker: 11 References 1.
Qing Zhou*, Xiaomin Yu*, Erkan Demirkaya, et al.
Biallelic hypomorphic mutations in a linear deubiquitinase define Otulipenia, an early-onset autoinflammatory disease.
Proceedings of the National Academy of Sciences, 2016 Sep 6;113(36):10127-32.
Reprint Instructions [Non-original articles] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated
.
