MCPIP1, alias Regnase-1 binds and cleaves mRNA of C/EBPβ

Lipert, Barbara; Wilamowski, Mateusz; Górecki, Andrzej; Jura, Jolanta

doi:10.1371/journal.pone.0174381

Cited by 22 publications

(27 citation statements)

References 39 publications

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“…This protein controls body fat by targeting the 3′ UTR of an mRNA encoding a fat-loss-promoting transcription factor, ETS-4. In turn, we showed that MCPIP1 negatively regulates adipogenesis by degrading transcripts coding for C/EBPβ [13,15]. Observations made by Li et al were similar to ours, demonstrating that transcripts coding for C/EBPβ and C/EBPδ are direct targets of MCPIP1 RNase [36].…”

Section: Discussionsupporting

confidence: 89%

“…Given the RNase activity of MCPIP1, negatively regulated transcripts/proteins could be direct downstream targets. However, these molecules may also be under the control of CEBPβ and PPARγ-two transcription factors that positively regulate adipocyte differentiation and are downregulated by MCPIP1 [13,15]. Besides its role in adipocyte differentiation, PPARγ is also thought to play a role in lipid metabolism, and insulin action through coordinated effects on gene transcription [38].…”

Section: Discussionmentioning

confidence: 99%

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Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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Obesity is considered a serious chronic disease, associated with an increased risk of developing cardiovascular diseases, non-alcoholic fatty liver disease and type 2 diabetes. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) is an RNase decreasing stability of transcripts coding for inflammation-related proteins. In addition, MCPIP1 plays an important role in the regulation of adipogenesis in vitro by reducing the expression of key transcription factors, including C/EBPβ. To elucidate the role of MCPIP1 in adipocyte biology, we performed RNA-Seq and proteome analysis in 3T3-L1 adipocytes overexpressing wild-type ( WT MCPIP1) and the mutant form of MCPIP1 protein ( D141N MCPIP1). Our RNA-Seq analysis followed by confirmatory Q-RT-PCR revealed that elevated MCPIP1 levels in 3T3-L1 adipocytes upregulated transcripts encoding proteins involved in signal transmission and cellular remodeling and downregulated transcripts of factors involved in metabolism. These data are consistent with our proteomic analysis, which showed that MCPIP1 expressing adipocytes exhibit upregulation of proteins involved in cellular organization and movement and decreased levels of proteins involved in lipid and carbohydrate metabolism. Moreover, MCPIP1 adipocytes are characterized by decreased level of insulin receptor, reduced insulin-induced Akt phosphorylation, as well as depleted Glut4 level and impaired glucose uptake. Overexpression of Glut4 in 3T3-L1 cells expressed WT MCPIP1 rescued adipogenesis. Interestingly, we found decreased level of MCPIP1 along with an increase in body mass index in subcutaneous adipose tissue. The presented data show a novel role of MCPIP1 in modulating insulin sensitivity in adipocytes. Overall, our findings demonstrate that MCPIP1 is an important regulator of adipogenesis and adipocyte metabolism.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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“…It was recently reported that C/EBPβ mRNA is a direct target of MCPIP1 RNase. 27 Our results further confirm that C/EBPβ is also regulated in macrophages. It has previously been reported that MCPIP1 RNase targets the 3′ UTR of its mRNA substrates, thereby promoting degradation.…”

Section: Resultssupporting

confidence: 81%

Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury

Huang

et al. 2017

Sig Transduct Target Ther

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Although systemic inflammatory responses attributable to infection may lead to significant lung injury, the precise molecular mechanisms leading to lung damage are poorly understood and therapeutic options remain limited. Here, we show that myeloid monocyte chemotactic protein-inducible protein 1 (MCPIP1) plays a central role in protecting against LPS-induced inflammation and lung injury. Myeloid-specific MCPIP1 knockout mice developed spontaneous inflammatory syndromes, but at a late age compared to global MCPIP1 knockout mice. Moreover, mice with a myeloid-specific deletion of MCPIP1 were extremely sensitive to LPS-induced lung injury due to overproduction of proinflammatory cytokines and chemokines. We identified C/EBPβ and C/EBPδ, two critical transcriptional factors that drive cytokine production and lung injury, as targets of MCPIP1 RNase. LPS administration caused MCPIP1 protein degradation in the lungs. Pharmacological inhibition of MALT1, a paracaspase that cleaves MCPIP1, by MI-2 selectively increased the MCPIP1 protein levels in macrophages and in the lungs. Meanwhile, administration of MI-2 protected mice from LPS-induced inflammation, lung injury and death. Collectively, these results indicate that myeloid MCPIP1 is central in controlling LPS-induced inflammation and lung injury. Pharmacological inhibition of MALT1 protease activity may be a good strategy to treat inflammatory diseases by enhancing MCPIP1 expression in myeloid cells.

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“…The activation of inflammatory cells is controlled on transcriptional and posttranscriptional levels by Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1, alias Regnase1), which is involved in negative regulation of inflammation through its endonuclease activity [Matsushita et al, 2009;Mizgalska et al, 2009] that shortens the half-life of selected pro-inflammatory cytokine transcripts (e.g., and mitigates their function [Mino et al, 2015;Lipert et al, 2017;Dobosz et al, 2016].…”

Section: Introductionmentioning

confidence: 99%

Deletion of Mcpip1 in Mcpip1^AlbKOmice recapitulates the phenotype of human primary biliary cholangitis

Kotlinowski

Hutsch

Czyżyńska-Cichoń

et al. 2020

Preprint

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Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1, alias Regnase1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Methods: Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC. 6-52-week-old Mcpip1fl/fl and Mcpip1AlbKO mice were used for immunohistochemical, biochemical and molecular tests. Results: We found that Mcpip1 deficiency in the liver recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1LysMKO mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1AlbKO livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1AlbKO mice was robust in 6-week-old and 52-week-old mice, but milder in 12-24-week-old mice, suggesting early prenatal origin of the phenotype and age-dependent progression of the disease. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1AlbKO mice showed 812 and 8 differentially expressed genes (DEGs), respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. Conclusions: The phenotype of Mcpip1AlbKO mice recapitulates most of the features of human PBC, and demonstrates early prenatal origin and age-dependent progression of PBC. Therefore, Mcpip1AlbKO mice provide a unique model for the study of PBC.

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MCPIP1, alias Regnase-1 binds and cleaves mRNA of C/EBPβ

Cited by 22 publications

References 39 publications

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury

Deletion of Mcpip1 in Mcpip1^AlbKOmice recapitulates the phenotype of human primary biliary cholangitis

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MCPIP1, alias Regnase-1 binds and cleaves mRNA of C/EBPβ

Cited by 22 publications

References 39 publications

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury

Deletion of Mcpip1 in Mcpip1AlbKOmice recapitulates the phenotype of human primary biliary cholangitis

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Deletion of Mcpip1 in Mcpip1^AlbKOmice recapitulates the phenotype of human primary biliary cholangitis