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The Journal of Neuroscience, September 15, 1999, 19(18):7770-7780
Neuronal Interleukin-16 (NIL-16): A Dual Function PDZ Domain
Protein
Cornelia
Kurschner and
Michisuke
Yuzaki
Department of Developmental Neurobiology, Saint Jude Children's
Research Hospital, Memphis, Tennessee 38105
Interleukin (IL)-16 is a proinflammatory cytokine that has
attracted widespread attention because of its ability to block HIV
replication. We describe the identification and characterization of a
large neuronal IL-16 precursor, NIL-16. The N-terminal half of NIL-16
constitutes a novel PDZ domain protein sequence, whereas the C terminus
is identical with splenocyte-derived mouse pro-IL-16. IL-16 has been
characterized only in the immune system, and the identification of
NIL-16 marks a previously unsuspected connection between the immune and
the nervous systems. NIL-16 is a cytosolic protein that is detected
only in neurons of the cerebellum and the hippocampus. The N-terminal
portion of NIL-16 interacts selectively with a variety of neuronal ion
channels, which is similar to the function of many other PDZ domain
proteins that serve as intracellular scaffolding proteins. Among the
NIL-16-interacting proteins is the class C 1 subunit of a mouse
brain calcium channel (mbC 1). The C terminus of NIL-16 can be
processed by caspase-3, resulting in the release of secreted IL-16.
Furthermore, in cultured cerebellar granule neurons undergoing
apoptosis, NIL-16 proteolysis parallels caspase-3 activation.
Cerebellar granule neurons express the IL-16 receptor CD4. Exposure of
these cells to IL-16 induces expression of the immediate-early gene,
c-fos, via a signaling pathway that involves tyrosine
phosphorylation. This suggests that IL-16 provides an autocrine
function in the brain. Therefore, we hypothesize that NIL-16 is a dual
function protein in the nervous system that serves as a secreted
signaling molecule as well as a scaffolding protein.
Key words:
IL-16; PDZ; caspase-3; cerebellar granule neurons; hippocampus; c-fos
Copyright © 1999 Society for Neuroscience 0270-6474/99/19187770-11$05.00/0
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