Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome

Background Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca2+-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly204Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals. Results In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding nor oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca2+ binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca2+ during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder. Conclusions We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca2+ binding during biosynthesis

Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells

<p>Abstract</p> <p>Background</p> <p>It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor γ (PPARγ); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC).</p> <p>Methods</p> <p>In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells.</p> <p>Results</p> <p>In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition.</p> <p>Conclusions</p> <p>Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC.</p

新規ヒトコレクチンCL-K1の生化学的解析

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Correction to: Pseudo-thermal anomalies in the shortwave infrared bands of the Himawari-8 AHI and their correction for volcano thermal observation

After publication of this article (Kaneko et al. 2018), it is noticed there is an error in Fig. 3b; the lower 2.3-µm band image is mistakenly removed. The correct Fig. 3 is given below

Pseudo-thermal anomalies in the shortwave infrared bands of the Himawari-8 AHI and their correction for volcano thermal observation

Abstract Volcanic eruptions bring high-temperature gas or magma to the surface. Therefore, thermal observations of volcanic eruptions can be used to investigate the timeline of eruptive sequences. Eruptive activity includes processes that can change over short periods of time, which is sometimes related to the eruptive mode or the timing of its transitions. If we could observe short-term eruptive processes by detecting thermal changes, this would be beneficial for analyzing the eruptive sequence of volcanoes. Himawari-8 is a meteorological geostationary satellite operating above the equator at a longitude of 140.7°E and carrying a newly developed sensor, the Advanced Himawari Imager (AHI). With its improved performance, the Himawari-8 AHI enables the collection of high-frequency thermal observations that had never been obtained before. However, while observing volcanoes with the AHI, we noticed a frequent thermal anomaly in the nighttime 1.6-µm and 2.3-µm images. Because this anomaly occurred regardless of volcanic activity, it was considered to be a pseudo-thermal anomaly. In-depth examination of the AHI observation data for several inactive volcanoes showed that the pseudo-thermal anomaly was often seen around the vernal and autumn eclipse periods, and its influence persisted for about 6 months of each year. Further, daily variation of the anomaly peaked when it was midnight in the areas around 140°E. At this time and position, the AHI was facing the sun, suggesting that the anomaly was caused by stray light. We devised a correction method by assuming that the observed thermal radiance in a pixel consists of components from the radiating volcanic ground surface and stray light contamination. The latter can be estimated using values from nearby inactive pixels. Thus, the component from the radiating volcanic ground surface can be obtained by subtracting the estimated stray light from the observed thermal radiance. We evaluated the validity of this method using data from the 2017 Nishinoshima eruption and found that it satisfactorily removed the stray light component. An adoption of this correction allowed us to use all nighttime 1.6-µm and 2.3-µm images obtained by the AHI, half of which were formerly unusable due to the degradation caused by stray light

Suppression of lipin-1 expression increases monocyte chemoattractant protein-1 expression in 3T3-L1 adipocytes

http://dx.doi.org/10.1016/j.bbrc.2011.10.060Lipin-1 plays a crucial role in the regulation of lipid metabolism and cell differentiation in adipocytes. Expression of adipose lipin-1 is reduced in obesity, and metabolic syndrome. However, the significance of this reduction remains unclear. This study investigated if and how reduced lipin-1 expression affected metabolism. We assessed mRNA expression levels of various genes related to adipocyte metabolism in lipin-1-depleted 3T3-L1 adipocytes by introducing its specific small interfering RNA. In lipin-1-depleted adipocytes, mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1) were significantly increased, although the other genes tested were not altered. The conditioned media from the cells promoted monocyte chemotaxis. The increase in MCP-1 expression was prevented by treatment with quinazoline or salicylate, inhibitors of nuclear factor-κB activation. Because MCP-1 is related to adipose inflammation and systemic insulin resistance, these results suggest that a reduction in adipose lipin-1 in obesity may exacerbate adipose inflammation and metabolism

Scavenger receptor CL-P1 mediates endocytosis by associating with AP-2μ2

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