Cutting Edge: Hypoxia-Induced Ubc9 Promoter Hypermethylation Regulates IL-17 Expression in Ulcerative Colitis.

Dysregulated IL-17 expression is central to the pathogenesis of several inflammatory disorders, including ulcerative colitis. We have shown earlier that SUMOylation of ROR-γt, the transcription factor for IL-17, regulates colonic inflammation. In this study, we show that the expression of Ubc9, the E2 enzyme that targets ROR-γt for SUMOylation, is significantly reduced in the colonic mucosa of ulcerative colitis patients.

Immune Dysfunction in Mendelian Disorders of POLA1 Deficiency.

POLA1 encodes the catalytic unit of DNA polymerase α, which together with the Primase complex launches the DNA replication process. While complete deficiency of this essential gene is presumed to be lethal, at least two conditions due to partial POLA1 deficiency have been described. The first genetic syndrome to be mapped to POLA1 was X-linked reticulate pigmentary disorder (XLPDR, MIM #301220), a rare syndrome characterized by skin hyperpigmentation, sterile multiorgan inflammation, recurrent infections, and distinct facial features.

Paneth cell-derived growth factors support tumorigenesis in the small intestine.

Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit.

NK cell defects in X-linked pigmentary reticulate disorder.

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease.

deficiency results in colitis susceptibility.

Inflammatory bowel disease (IBD) affects 1.5-3.0 million people in the United States.

Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.

Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways.

Mosaic Tetrasomy 9p Associated With Inflammatory Bowel Disease.

The genetic basis of inflammatory bowel disease remains to be elucidated completely. Here we report on a patient with inflammatory bowel disease who has mosaic tetrasomy of the short arm of chromosome 9, a genomic region that harbours the type I interferon gene cluster. We show that increased interferon activation is present in peripheral blood and intestinal tissue from this patient, similar to previous reports of autoinflammatory organ damage driven by interferon activation in other patients with this chromosomal abnormality.

Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism.

Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10 nucleotides/min with an error rate of less than one per million nucleotides polymerized.

Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation.

Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis.

DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

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-α.

Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question.

The question whether or not "viruses are alive" has caused considerable debate over many years. Yet, the question is effectively without substance because the answer depends entirely on the definition of life or the state of "being alive" that is bound to be arbitrary. In contrast, the status of viruses among biological entities is readily defined within the replicator paradigm.

Methodology to study NF-κB/RelA ubiquitination in vivo.

Nuclear factor-kappa B (NF-κB) is a family of transcription factors that regulate immune responses, cell proliferation, differentiation, and survival. Activity of the NF-κΒ pathway on a cellular level is tightly controlled through various mechanisms, one of which is the ubiquitin-dependent degradation of chromatin-bound NF-κB subunits. In general, the ubiquitination of NF-κB regulates the duration of gene transcription activated in response to inflammatory signals.

Detection of IκB degradation dynamics and IκB-α ubiquitination.

The NF-κB 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-κB transcription factors are sequestered in the cytoplasm by the IκB family of proteins. Various pro-inflammatory stimuli result in the phosphorylation and subsequent ubiquitination of IκBs.

Microbes on the edge of Occam's razor.

Our body harbors hundreds of microbial species and contains many more bacterial than human cells. These microbes are not passive riders but rather a vital component of the organism. The human microbiota affects our health in multiple ways, both positively and negatively.

COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A.

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.

Bimolecular affinity purification: a variation of TAP with multiple applications.

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.

Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.

Background & Aims: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings.

A bird's-eye view of autophagy.

Autophagy is a process in which a eukaryotic (but not prokaryotic) cell destroys its own components through the lysosomal machinery. This tightly regulated process is essential for normal cell growth, development, and homeostasis, serving to maintain a balance between synthesis and degradation, resulting in the recycling of cellular products. Here we try to expand the concept of autophagy and define it as a general mechanism of regulation encompassing various levels of the biosphere.

CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.

NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation.

COMMD1 (copper metabolism MURR1 domain-containing protein 1) regulates Cullin RING ligases by preventing CAND1 (Cullin-associated Nedd8-dissociated protein 1) binding.

Cullin RING ligases (CRLs), the most prolific class of ubiquitin ligase enzymes, are multimeric complexes that regulate a wide range of cellular processes. CRL activity is regulated by CAND1 (Cullin-associated Nedd8-dissociated protein 1), an inhibitor that promotes the dissociation of substrate receptor components from the CRL. We demonstrate here that COMMD1 (copper metabolism MURR1 domain-containing 1), a factor previously found to promote ubiquitination of various substrates, regulates CRL activation by antagonizing CAND1 binding.