Ribosomopathies are a diverse subset of diseases caused by reduced expression of, or mutations in, factors necessary for making ribosomes, the protein translation machinery in the cell. Despite the ...ubiquitous need for ribosomes in all cell types, ribosomopathies manifest with tissue-specific defects and sometimes increased cancer susceptibility, but few treatments target the underlying cause. By highlighting new research in the field, we review current hypotheses for the basis of this tissue specificity. Based on new work, we broaden our understanding of the role of ribosome biogenesis in diverse tissue types throughout embryonic development. We also pose the question of whether previously described human conditions such as aging can be at least partially attributed to defects in making ribosomes.
Ribosomopathies are disorders of making ribosomes that manifest in afflicted humans with tissue-specificity.Several new ribosomopathies have recently been discovered, helping to reveal the link between ribosome biogenesis and human development.The specialized ribosomes hypothesis states that the tissue-specific defects of ribosomopathies are due to ribosome heterogeneity caused by changes in ribosomal protein composition or modification, rRNA composition or modification, or accessory protein binding.The ribosome concentration hypothesis states that the tissue-specific defects of ribosomopathies are due to changes in mRNA translation as a consequence of reduced ribosome number.Dysregulation of nucleolar activity is associated with aging and neurodegeneration, suggesting that these disorders may perhaps also be ribosomopathies.
Nucleolar function and the cellular response to DNA damage have long been studied as distinct disciplines. New research and a new appreciation for proteins holding multiple functional roles, however, ...is beginning to change the way we think about the crosstalk among distinct cellular processes. Here, we focus on the crosstalk between the DNA damage response and the nucleolus, including a comprehensive review of the literature that reveals a role for conventional DNA repair proteins in ribosome biogenesis, and conversely, ribosome biogenesis proteins in DNA repair. Furthermore, with recent advances in nucleolar proteomics and a growing list of proteins that localize to the nucleolus, it is likely that we will continue to identify new DNA repair proteins with a nucleolar-specific role. Given the importance of ribosome biogenesis and DNA repair in essential cellular processes and the role that they play in diverse pathologies, continued elucidation of the overlap between these two disciplines will be essential to the advancement of both fields and to the development of novel therapeutics.
Background
Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL‐4 and IL‐13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL‐4 ...or IL‐13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL‐13 signal.
Methods
We systematically identified periostin‐dependent expression profile using DNA microarrays. We then investigated whether IL‐24 downregulates filaggrin expression downstream of the IL‐13 signals and whether IL‐13‐induced IL‐24 expression and IL‐24‐induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL‐24 and activation of STAT3 in mite‐treated mice and in AD patients.
Results
We identified IL‐24 as an IL‐13‐induced molecule in a periostin‐dependent manner. Keratinocytes are the main IL‐24‐producing tissue‐resident cells stimulated by IL‐13 in a periostin‐dependent manner via STAT6. IL‐24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL‐13/periostin pathway. Wild‐type mite‐treated mice showed significantly enhanced expression of IL‐24 and activation of STAT3 in the epidermis, which disappeared in both STAT6‐deficient and periostin‐deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL‐24 expression was enhanced in the epidermis of skin tissues taken from AD patients.
Conclusions
The IL‐13/periostin pathway induces IL‐24 production in keratinocytes, playing an important role in barrier dysfunction in AD.
Epithelial barrier dysfunction is important in the pathogenesis of atopic dermatitis. We show that IL‐24 produced in keratinocytes downstream of IL‐13 and periostin downregulates filaggrin expression leading to barrier dysfunction.
Synthetic saponite containing a photosensitizing metal complex was complexed with colloidal anatase and used for the visible light photocatalytic reaction of aqueous benzene to phenol. The addition ...of phenol to the initial aqueous benzene solution was effective in improving the reaction yield and the product selectivity.
Synthetic saponite containing a photosensitizing metal complex was complexed with colloidal anatase and used for the visible light photocatalytic reaction of aqueous benzene to phenol.
Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal ...levels of hematologic measures but does not treat the underlying systemic disease.
We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).
A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.
Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 adults and NCT00844844 adolescents; C08-003 ClinicalTrials.gov numbers, NCT00838513 adults and NCT00844428 adolescents).
Ribosome biogenesis is a highly regulated, essential cellular process. Although studies in yeast have established some of the biological principles of ribosome biogenesis, many of the intricacies of ...its regulation in higher eukaryotes remain unknown. To understand how ribosome biogenesis is globally integrated in human cells, we conducted a genome-wide siRNA screen for regulators of nucleolar number. We found 139 proteins whose depletion changed the number of nucleoli per nucleus from 2–3 to only 1 in human MCF10A cells. Follow-up analyses on 20 hits found many (90%) to be essential for the nucleolar functions of rDNA transcription (7), pre-ribosomal RNA (pre-rRNA) processing (16), and/or global protein synthesis (14). This genome-wide analysis exploits the relationship between nucleolar number and function to discover diverse cellular pathways that regulate the making of ribosomes and paves the way for further exploration of the links between ribosome biogenesis and human disease.
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•Genome-wide siRNA screen for human proteins that regulate nucleolar number•Biochemical analyses of the 139 hits found roles for 18/20 in ribosome biogenesis•The results reveal an orchestrated gene network that co-regulates ribosome assembly
Ribosome biogenesis in the nucleolus is essential for cell growth in all eukaryotic cells. Farley-Barnes et al. use an unbiased genome-wide siRNA screen in human cells to discover proteins required to make ribosomes, connecting unexpected pathways to ribosome assembly.
The main components of the essential cellular process of eukaryotic ribosome biogenesis are highly conserved from yeast to humans. Among these, the U3 Associated Proteins (UTPs) are a small subunit ...processome subcomplex that coordinate the first two steps of ribosome biogenesis in transcription and pre-18S processing. While we have identified the human counterparts of most of the yeast Utps, the homologs of yeast Utp9 and Bud21 (Utp16) have remained elusive. In this study, we find that NOL7 is the likely ortholog of Bud21. Previously described as a tumour suppressor through regulation of antiangiogenic transcripts, we now show that NOL7 is required for early pre-rRNA accumulation and pre-18S rRNA processing in human cells. These roles lead to decreased protein synthesis and induction of the nucleolar stress response upon NOL7 depletion. Beyond Bud21's nonessential role in yeast, we establish human NOL7 as an essential UTP that is necessary to maintain both early pre-rRNA levels and processing.
The aim of this study was to characterize the standard morphology of the oral commissure and to describe the changes after reconstruction in patients with through-and-through cheek defects involving ...the oral commissure. Indices for the morphological analyses of the commissure were derived from examinations of 50 normal Japanese volunteers. Ten patients with full-thickness cheek defects involving the commissure were then evaluated. All of these patients underwent free flap reconstruction with vermilion advancement flaps from the remaining vermilion. The morphology of the commissure with the mouth closed was classified based on the point of entrance of the vermilion into the oral cavity. In normal volunteers, the commissure pattern consisting of the entrance of the upper vermilion into the oral cavity before the lower vermilion and just prior to forming the oral commissure was considered to be the standard. However, in the reconstructed cases, there was an increase in the pattern in which the lower vermilion enters the oral cavity before the upper vermilion for the remaining commissure postoperatively, especially when the lower lip defects were greater than those of the upper lip. It is important to refer not only to the standard morphology of the commissure, but also to the changes according to the extent of resection and the method of reconstruction.
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