A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling.

A stochastic lateral signaling interaction between two developing Caenorhabditis elegans AWC olfactory neurons causes them to take on asymmetric patterns of odorant receptor expression, called AWC(OFF) and AWC(ON). Here we show that the AWC lateral signaling gene tir-1 (previously known as nsy-2) encodes a conserved post-synaptic protein that specifies the choice between AWC(OFF) and AWC(ON). Genetic evidence suggests that tir-1 acts downstream of a voltage-gated calcium channel and CaMKII (UNC-43) to regulate AWC asymmetry via the NSY-1(ASK1) p38/JNK MAP (mitogen-activated protein) kinase cascade. TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression. Temperature-shift experiments indicate that tir-1 affects AWC during a critical period late in embryogenesis, near the time of AWC synapse formation. TIR-1 is a multidomain protein with a TIR (Toll-interleukin-1 receptor) domain that activates signaling, SAM repeats that mediate localization to post-synaptic regions of axons, and an N-terminal inhibitory domain. TIR-1 and other TIR proteins are implicated in vertebrate and invertebrate innate immunity, as are NSY-1/ASK1 kinases, so this pathway may also have a conserved function in immune signaling.