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Articles by N Heise
Total Records ( 2 ) for N Heise
  N Heise , D Singh , H van der Wel , S. O Sassi and C. M West
 

Trypanosoma cruzi, the causative agent of Chagas disease, is surrounded by a mucin coat that plays important functions in parasite survival/invasion and is extensively O-glycosylated by Golgi and cell surface glycosyltransferases. The addition of the first sugar, -N-acetylglucosamine (GlcNAc) linked to Threonine (Thr), is catalyzed by a polypeptide -GlcNAc-transferase (pp-GlcNAcT) which is unstable to purification. Here, a comparison of the genomes of T. cruzi and Dictyostelium discoideum, an amoebazoan which also forms this linkage, identified two T. cruzi genes (TcOGNT1 and TcOGNT2) that might encode this activity. Though neither was able to complement the Dictyostelium gene, expression in the trypanosomatid Leishmania tarentolae resulted in elevated levels of UDP-[3H]GlcNAc:Thr-peptide GlcNAc-transferase activity and UDP-[3H]GlcNAc breakdown activity. The ectodomain of TcOGNT2 was expressed and the secreted protein was found to retain both activities after extensive purification away from other proteins and the endogenous activity. Product analysis showed that 3H was transferred as GlcNAc to a hydroxyamino acid, and breakdown was due to hydrolysis. Both activities were specific for UDP-GlcNAc relative to UDP-GalNAc and were abolished by active site point mutations that inactivate a related Dictyostelium enzyme and distantly related animal pp-GalNAcTs. The peptide preference and the alkaline pH optimum were indistinguishable from those of the native activity in T. cruzi microsomes. The results suggest that mucin-type O-glycosylation in T. cruzi is initiated by conserved members of CAZy family GT60, which is homologous to the GT27 family of animal pp-GalNAcTs that initiate mucin-type O-glycosylation in animals.

  I. M Zemtsova , N Heise , H Frohlich , S. M Qadri , Y Kucherenko , K. M Boini , D Pearce , E Shumilina and F. Lang
 

Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 (sgk3–/–) and their wild-type littermates (sgk3+/+). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca2+ and entry of extracellular Ca2+. Influx of extracellular Ca2+ but not Ca2+ release from intracellular stores was significantly blunted in sgk3–/– BMMCs compared with sgk3+/+ BMMCs. Antigen stimulation further led to a rapid increase of a K+-selective conductance in sgk3+/+ BMMCs, an effect again blunted in sgk3–/– BMMCs. In contrast, the Ca2+ ionophore ionomycin activated K+ currents to a similar extent in sgk3–/– and in sgk3+/+ BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3–/– BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3–/– compared with sgk3+/+ mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3–/– than in sgk3+/+ mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.

 
 
 
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