The mast cell transmembrane adaptor protein NLAT (non-T-cell activation linker) functions as both a negative and positive regulator of FcRI-mediated signaling.
Cross-linking of the high-affinity receptor for IgE (FcRI) at the cell surface of mast cells initiates signalling cascades that result in mast-cell degranulation and cytokine production. Mast cells express two transmembrane adaptor proteins: linker for activation of T cells (LAT) and non-T-cell activation linker (NTAL; also known as LAB). LAT-deficient mast cells have impaired responses to FcRI engagement. However, surprising new data from two groups show that NTAL functions as both a negative and positive regulator of FcRI-mediated signalling.
NTAL and LAT have a similar protein-domain organization, and previous studies have shown that there is redundancy between these two transmembrane adaptor proteins for several functions. Therefore, both groups investigated the possibility that NTAL mediates the residual signalling activity in LAT-deficient mast cells, by generating NTAL-deficient mice and mice deficient in both NTAL and LAT. Using a passive anaphylaxis assay — in which mice are inoculated first with hapten-specific IgE and then the hapten conjugated to a carrier protein — both groups observed that NTAL-deficient mice had higher serum levels of histamine than similarly treated wild-type mice. Further evidence that NTAL has a negative influence on mast-cell function was provided by two observations: first, bone-marrow-derived mast cells from NTAL-deficient mice showed increased FcRI-mediated degranulation; and second, Zhu et al. detected increased production of several cytokines, including interleukin-2 (IL-2), IL-3, IL-4 and tumour-necrosis factor, in response to FcRI engagement.
This increased mast-cell function following FcRI engagement in the absence of NTAL correlated with increased phosphorylation of phospholipase C-1 (PLC-1) and PLC-2, increased phosphorylation of extracellular signal-regulated kinase (ERK) and increased intracellular calcium levels. In addition, Volná et al. observed increased phosphatidylinositol 3-kinase activity and increased LAT phosphorylation. Because both groups observed that more LAT could be found in lipid rafts in the absence of NTAL, and because Zhu et al. also observed the converse (that is, that more NTAL was present in lipid rafts in the absence of LAT), the authors of both studies suggest that NTAL negatively regulates mast-cell signalling by competing with LAT for lipid-raft localization.
In contrast to the inhibitory role of NTAL in FcRI-mediated signalling, which is indicated by the phenotype of mast cells derived from NTAL-deficient mice, both groups observed that mast cells derived from mice deficient in both NTAL and LAT were more severely impaired in their ability to signal and respond after FcRI engagement than mast cells deficient in LAT alone. So, these data indicate that NTAL has a positive role in FcRI-mediated signalling.
These studies identify an unexpected role for the transmembrane adaptor protein NTAL as both a negative and a positive regulator of FcRI-mediated signalling in mouse mast cells. Further studies are required to address the large number of questions that arise from these data. For example, how does NTAL compete with LAT for raft localization and what determines whether NTAL functions positively or negatively in FcRI-mediated signalling?
Karen Honey
References
Zhu, M., Liu, Y., Koonpaew, S., Granillo, O. & Zhang, W. Positive and negative regulation of FcRI-mediated signaling by the adaptor protein LAB/NTAL. J. Exp. Med.200, 991–1000 (2004) | Article | PubMed |
Volná, P. et al. Negative regulation of mast cell signaling and function by the adaptor LAB/NTAL. J. Exp. Med.200, 1001–1013 (2004). | Article | PubMed |
Hoejí, V., Zhang, W. & Schraven, B. Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nature Rev. Immunol.4, 603–616 (2004) | Article | PubMed |
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í, V., Zhang, W. & Schraven, B. Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nature Rev. Immunol. 4, 603–616 (2004)