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Non‐T cell activation linker (NTAL) proteolytic cleavage as a terminator of activatory intracellular signals

Non‐T cell activation linker is an adaptor protein that is tyrosine phosphorylated upon cross‐linking of immune receptors expressed on B lymphocytes, NK cells, macrophages, basophils, or mast cells, allowing the recruitment of cytosolic mediators for downstream signaling pathways. Fas receptor acts mainly as a death receptor, and when cross‐linked with Fas ligand, many proteins are proteolytically cleaved, including several signaling molecules in T and B cells. Fas receptor triggering also interferes with TCR intracellular signals, probably by means of proteolytic cleavage of several adaptor proteins. We have previously found that the adaptor linker for activation of T cells, evolutionarily related to non‐T cell activation linker, is cleaved upon proapoptotic stimuli in T lymphocytes and thymocytes, in a tyrosine phosphorylation‐dependent fashion. Here, we describe non‐T cell activation linker proteolytic cleavage triggered in human B cells and monocytes by Fas cross‐linking and staurosporine treatment. Non‐T cell activation linker is cleaved, producing an N‐terminal fragment of ∼22 kDa, and such cleavage is abrogated in the presence of caspase 8/granzyme B and caspase 3 inhibitors. Moreover, we have identified an aspartic acid residue at which non‐T cell activation linker is cleaved, which similar to linker for activation of T cells, this aspartic acid residue is located close to tyrosine and serine residues, suggesting an interdependence of phosphorylation and proteolytic cleavage. Consistently, induction of non‐T cell activation linker phosphorylation by pervanadate inhibits its cleavage. Interestingly, the truncated isoform of non‐T cell activation linker, generated after cleavage, has a decreased signaling ability when compared with the full‐length molecule. Altogether, our results suggest that cleavage of transmembrane adaptors constitutes a general mechanism for signal termination of immune receptors.