Members of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and mu-rine mast cells. The IL-33R-induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH 2-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33-induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitu-tively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses. (Blood. 2010; 115(19):3899-3906)
Bovine viral diarrhoea virus (BVDV) is a pestivirus within the family Flaviviridae. In contrast to the members of the genus flavivirus, nothing is known about the viral entry route for pestiviruses. In this study, the process of BVDV infection following attachment to the cell surface was examined. BVDV clearly co-localizes with clathrin, with early endosome antigen-1 (EEA-1), an early endosome marker, and also with lysosomal-associated membrane protein-2 (LAMP-2), a lysosomal marker. BVDV internalization is inhibited by compounds that block clathrin- but not caveolae-dependent endocytosis. These findings demonstrate that BVDV enters the cells via the clathrin-coated pit pathway.
Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.
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