Inhibiting the Restocking of the Store

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Science  14 Jul 2006:
Vol. 313, Issue 5784, pp. 149
DOI: 10.1126/science.313.5784.149c

Golli proteins, which are generated by alternative splicing from the gene that encodes myelin basic proteins (which are found only in the nervous system), are expressed not only in the nervous system but also in immune system tissues. Feng et al., who previously showed that golli negatively regulates T cell activation, establish that this occurs via the inhibition of calcium influx. When stimulated with antibody directed against CD3 (anti-CD3) or with anti-CD3 plus anti-CD28, golli-deficient T cells proliferated more vigorously than did wild-type cells. Similarly, golli-deficient cells stimulated with anti-CD3 plus anti-CD20 produced more interleukin-2 (a T cell growth factor) than did wild-type cells. No differences between golli-deficient and wild-type T cells in extracellular receptor-activated kinase (ERK) or Jun N-terminal kinase (JNK) activation in response to anti-CD3 stimulation were apparent. On the other hand, the increase in intracellular calcium upon stimulation was enhanced. Calcium imaging in the presence or absence of extracellular calcium and thapsigargin suggested that golli inhibited calcium influx through store-operated calcium channels (these plasma membrane conduits open in response to a signal that calcium levels in internal compartments need replenishing). Moreover, patch-clamp analysis of golli-deficient cells revealed increased inward calcium current in response to store depletion. A portion of T cell golli protein was associated with the plasma membrane, and experiments in which cells were transfected with either wild-type golli protein or a myristoylation-deficient mutant indicated that membrane association was required for golli to inhibit calcium influx. Thus, the authors conclude that golli acts as a negative regulator of T cell activation by means of a mechanism completely distinct from that of other regulators of T cells. — EMA

Immunity 24, 717 (2006).

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