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DNA polymerase-Î± regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. - Nature immunology
Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-Î±. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.
CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. - Nature communications
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling. - The Journal of cell biology
Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD-CCDC22-CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family.Â© 2015 Li et al.
Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease. - Digestive diseases and sciences
Both obesity and inflammatory bowel disease (IBD) are highly prevalent in Western societies. IBD, including Crohn's disease (CD) and ulcerative colitis (UC), has been historically associated with cachexia and malnutrition. It is uncertain how obesity, a chronic pro-inflammatory state, may impact the course of IBD.The aim of this study was to report the prevalence of obesity in patients with IBD in a metropolitan US population and to assess the impact of obesity on disease phenotypes, treatment, and surgical outcomes in IBD patients.We reviewed the medical records of patients identified from the IBD registries of the Dallas Veterans Affairs Medical Center and Parkland Health and Hospital Systems who were seen from January 1, 2000, to December 31, 2012.Of 581 identified IBD patients, 32.7Â % were obese (BMIÂ â‰¥Â 30) and 67.6Â % were non-obese (BMIÂ <Â 30). There were 297 (51.1Â %) patients with CD and 284 (48.9Â %) patients with UC. The rate of obesity was 30.3Â % among CD patients and 35.2Â % among UC patients. Overall, obese patients were significantly less likely to receive anti-TNF treatment, undergo surgery, or experience a hospitalization for their IBD than their non-obese counterparts (55.8 vs. 72.1Â %, pÂ =Â .0001).Obesity is highly prevalent in our IBD patients, paralleling the obesity rates in the US population. Clinical outcomes were significantly different in obese versus non-obese patients with IBD. Despite the plausible mechanisms whereby obesity might exacerbate IBD, we have found that obesity (as defined by BMI) is a marker of a less severe disease course in IBD.
Methodology to study NF-ÎºB/RelA ubiquitination in vivo. - Methods in molecular biology (Clifton, N.J.)
Nuclear factor-kappa B (NF-ÎºB) is a family of transcription factors that regulate immune responses, cell proliferation, differentiation, and survival. Activity of the NF-ÎºÎ’ pathway on a cellular level is tightly controlled through various mechanisms, one of which is the ubiquitin-dependent degradation of chromatin-bound NF-ÎºB subunits. In general, the ubiquitination of NF-ÎºB regulates the duration of gene transcription activated in response to inflammatory signals. In this article, we present protocols to examine the in vivo ubiquitination status of RelA, a critical protein of the NF-ÎºB family.
Detection of IÎºB degradation dynamics and IÎºB-Î± ubiquitination. - Methods in molecular biology (Clifton, N.J.)
The NF-ÎºB signaling pathway is a primary regulator of inflammation that has been implicated in the pathogenesis of immune disorders and cancer. This signaling network is strictly regulated; in a nonactivated state, NF-ÎºB transcription factors are sequestered in the cytoplasm by the IÎºB family of proteins. Various pro-inflammatory stimuli result in the phosphorylation and subsequent ubiquitination of IÎºBs. These events lead to rapid degradation of IÎºB and allow translocation of the transcription factors to the nucleus. Therefore, ubiquitination and degradation of IÎºBs are critical steps in NF-ÎºB pathway activation and can serve as a quantitative parameter to assess pathway activation. In this article, we present a detailed protocol for the quantification of in vivo ubiquitination and turnover of IÎºB-Î± in response to a variety of cellular stimuli.
COMMD1 regulates inflammation and colitis-associated cancer progression. - Oncoimmunology
NF-ÎºB is a master transcriptional regulator of inflammation that plays an important role in oncogenesis, particularly in tumors that arise in the context of inflammation. Copper metabolism MURR1 domain-containing 1 (COMMD1) is a negative regulator of NF-ÎºB. Recent genetic-based studies in both mice and human patients indicate that COMMD1 has an important role in controlling intestinal inflammation and constraining progression to colitis-associated cancer.
COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A. - Molecular biology of the cell
COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.Â© 2015 Phillips-Krawczak, Singla, etÂ al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attributionâ€“Noncommercialâ€“Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
A cell-type-specific role for murine Commd1 in liver inflammation. - Biochimica et biophysica acta
The transcription factor NF-ÎºB plays a critical role in the inflammatory response and it has been implicated in various diseases, including non-alcoholic fatty liver disease (NAFLD). Although transient NF-ÎºB activation may protect tissues from stress, a prolonged NF-ÎºB activation can have a detrimental effect on tissue homeostasis and therefore accurate termination is crucial. Copper Metabolism MURR1 Domain-containing 1 (COMMD1), a protein with functions in multiple pathways, has been shown to suppress NF-ÎºB activity. However, its action in controlling liver inflammation has not yet been investigated. To determine the cell-type-specific contribution of Commd1 to liver inflammation, we used hepatocyte and myeloid-specific Commd1-deficient mice. We also used a mouse model of NAFLD to study low-grade chronic liver inflammation: we fed the mice a high fat, high cholesterol (HFC) diet, which results in hepatic lipid accumulation accompanied by liver inflammation. Depletion of hepatocyte Commd1 resulted in elevated levels of the NF-ÎºB transactivation subunit p65 (RelA) but, surprisingly, the level of liver inflammation was not aggravated. In contrast, deficiency of myeloid Commd1 exacerbated diet-induced liver inflammation. Unexpectedly we observed that hepatic and myeloid Commd1 deficiency in the mice both augmented hepatic lipid accumulation. The elevated levels of proinflammatory cytokines in myeloid Commd1-deficient mice might be responsible for the increased level of steatosis. This increase was not seen in hepatocyte Commd1-deficient mice, in which increased lipid accumulation appeared to be independent of inflammation. Our mouse models demonstrate a cell-type-specific role for Commd1 in suppressing liver inflammation and in the progression of NAFLD.Copyright Â© 2014 Elsevier B.V. All rights reserved.
Bimolecular affinity purification: a variation of TAP with multiple applications. - Methods in molecular biology (Clifton, N.J.)
The identification of true interacting partners of any given bait can be plagued by the nonspecific purification of irrelevant proteins. To avoid this problem, Tandem Affinity Purification (TAP) is a widely used procedure in molecular biology as this reduces the chance of nonspecific proteins being present in the final preparation. In this approach, two different affinity tags are fused to the protein bait. Herein, we review in detail a variation on the TAP procedure that we have previously developed, where the affinity moieties are placed on two different proteins that form a complex in vivo. This variation, which we refer to as Bimolecular Affinity Purification (BAP), is suited for the identification of specific molecular complexes marked by the presence of two known proteins. We have utilized BAP for characterization of molecular complexes and evaluation of proteins interaction. Another application of BAP is the isolation of ubiquitin-like proteins (UBL)-modified fractions of a given protein and characterization of the lysine-acceptor site and structure of UBL-chains.
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