O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.Regulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3–6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in secretion, the mechanisms by which this protein modification affects secretion are currently unknown. Here, we demonstrate that O-glycosylation influences secretion and secretory vesicle formation by glycosylating the essential endoplasmic reticulum (ER)/Golgi protein Tango1, and conferring protection from furin-mediated proteolysis. Interestingly, secretory defects caused by the loss of O-glycosylation could be rescued by reducing the activity of a specific furin (Dfur2) in vivo. Our results elucidate a novel regulatory paradigm whereby the competing activities of an O-glycosyltransferase and a furin control secretion and secretory vesicle formation. Moreover, this finding offers a potential treatment for disorders of glycosylation by modulating the activity of specific proteases in vivo.     

Dental lesions in tumoral calcinosis

Tumoral calcinosis (TC) is a rare inherited autosomal dominant metabolic disease manifested by elevated serum phosphorus and 1,25 dihydroxyvitamin D levels and periarticular cystic and solid tumorous calcifications. The dental findings in a large family have been critical in determining the genetic transmission of the condition. Radiographically the teeth have short bulbous roots, pulp stones and partial obliteration of the pulp cavity. Histologically, coronal dentin and a variable amount of radicular dentin appears to be deposited regularly. At nonspecific points the developing radicular dentin appears to encounter a mass of calcified material and proceed to grow around it. This mass has a unique histologic pattern with ovoid spaces surrounded by amorphous calcification. At levels of further root development the radicular dentin has an irregular bending tubule arrangement. The dental lesion of TC appears to be different from that of radicular dentin dysplasia in histologic structure and in the method of initiation of the dentin defect. These data suggest that the specific dental lesion is a new phenotypic marker for TC.     

Auricular ossification

A patient with extensive bilateral auricular ossification presented with chondrodermatitis nodularis helicis on one side. The condition was otherwise asymptomatic. Ossification was delected on radiological and histological examination. Underlying medical conditions were nut Pound. We believe this developed as a eon-sequence of cold injury. Auricular ossification is an unusual cause of the so-called petrified external ear, in which the subcutaneous tissue is stony hard, it is more commonly caused by dystrophic calcification. Calcification and ossification are clinically identical and histological examination is required to definitively differentiate them.     

女性冠心病患者雌激素、Notch1水平与冠状动脉钙化严重程度的关系

目的 探讨绝经后女性冠状动脉粥样硬化性心脏病（CAD)患者血清雌激素水平及外周血单个核细胞Notch1表达水平与冠状动脉钙化严重程度的关系。方法 选择2016年1月至2017年6月在我院心内科住院并诊断为CAD的绝经后女性患者266例,入选病例均接受320排螺旋CT心脏冠状动脉成像检查,计算冠状动脉钙化积分（CCS）,其中CCS=0的患者46例作为对照组,CCS＞0的患者按CCS的均值水平（CCS=95.4)分为低钙化积分组（CCS＜95.4）组113例与高钙化积分组（CCS≥95.4）组107例,检测患者外周静脉血血清雌二醇E2水平及外周血单个核细胞Notch1表达水平。结果 高钙化积分组患者血清雌二醇水平显著低于其他两组患者（9.01±1.33 pg/mL-1 比9.95±1.42 pg/mL-1比 11.21±1.76 pg/mL-1）,而外周血单核细胞Notch1表达水平高于另外两组患者（6.93±0.71 比6.15±0.68比5.89±0.65）,差异均有统计学意义（P<0.05）。Spearman相关分析显示存在冠脉钙化的绝经后女性CAD患者血清雌二醇水平与外周血单个核细胞Notch1表达水平成负相关（r=-0.467, P<0.01）。多因素Logistic回归分析显示血清雌二醇水平及外周血单个核细胞Notch1表达水平均是影响绝经后女性CAD患者冠脉钙化严重程度的独立危险因素（P＜0.05）。结论 绝经后女性CAD患者雌激素水平降低是促进冠脉钙化的重要因素,雌激素通过干预Notch1信号通路表达可能是影响冠脉钙化形成和进展的重要机制之一。     

Calcinosis cutis: diagnosis by fine needle aspiration cytology--a rare case report

Calcinosis cutis is characterized by deposition of calcium salts in the subcutaneous tissues in the body. In this study, we described a case of calcinosis cutis that was diagnosed by fine needle aspiration (FNA) in a 15-year-old male. The patient presented with multiple nodules over right forearm and right knee. FNA smears showed flakes of amorphous material indicating calcium along with few macrophages. The presence of amorphous calcium salts along with histiocytes in the appropriate clinical settings is diagnostic of calcinosis cutis.     

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肿瘤样钙盐沉着症(tumoral calcinosis,TC)是一种非肿瘤性的无定形钙盐沉积,好发于大关节附近,偶位于手、足或膝部,位于头颈部罕见。中山大学光华口腔医学院.附     

Spontaneous abdominal hematoma in dermatomyositis

Dermatomyositis is associated with a number of systemic manifestations and diseases. We present 2 patients with dermatomyositis, aged 11 and 50 years, who developed acute abdominal pain, both a result of spontaneous hemorrhage. Hemorrhage was detectable by physical examination in one and on computed tomography scan of the abdomen in the other. Both patients made a full recovery with supportive treatment. While the cause of the hemorrhage was uncertain, in 1 patient massive calcinosis of the abdominal wall was present, and trauma may have been the precipitant. Spontaneous abdominal hematoma is a cause of acute abdominal pain in patients with dermatomyositis, and surgery may be avoided if the diagnosis is recognized. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1800–1803, 1998     

Using imaging methods to assess severe calcinosis in juvenile dermatomyositis: A case report

Calcinosis and lipodystrophy are severe complications of juvenile dermatomyositis (JDM). Up to 20% of patients have calcinosis, and the onset of calcinosis usually occurs 1 to 3 years after that of the illness. We report a case of JDM with severe complications of calcinosis and lipodystrophy, and we assess calcinosis using a variety of imaging methods. To evaluate the patient's inflammatory state, bone scintigraphy was performed, which demonstrated increased uptake in the right scapula, in addition, multiple calcifications are present subcutaneously on the shoulder and back, and inflammatory imaging features are also present in the right knee joint.