Ready, STAT, go: transcription factors on the move

Abstract

In this issue of The EMBO Journal, Ben-Yaakov et al (2012) explore the contribution of transcription factors (TFs) in directly communicating information about injury between the axon and the nucleus. They show that multiple TFs bind the retrograde molecular motor dynein in injured axons. Focusing on one TF family, the authors reveal that STAT3 is locally translated and activated in injured axons, and then transported retrogradely to the nucleus to promote survival of peripheral sensory neurons.Recovery from peripheral nerve injury can be relatively successful, but the insult can also lead to permanent neurological deficits including failure of reinnervation and neuronal loss. What determines whether a neuron survives and regenerates after injury? The existence of injury signals ascending from the axon to the cell body was proposed to account for the changes observed in sensory neurons' cell bodies following injury (Cragg, 1970). Much progress has since been made to reveal the identities of such injury signals (Abe and Cavalli, 2008). Downstream of positive injury signals, TFs control the expression of regeneration-associated genes. The involvement of nuclear localization signals to target proteins to the axonal retrograde transport system (Schmied et al, 1993) and the role of importin nuclear transport factors in injury signalling (Yudin et al, 2008) suggests that TFs themselves might be involved in direct communication between injured axon and the nucleus, a possibility that Ben-Yaakov and colleagues directly test in the current issue of The EMBO Journal.The authors used computational tools to analyse TF binding sites (TFBS) in a previously generated dorsal root ganglion (DRG) microarray data set (Michaelevski et al, 2010). This analysis revealed a list of TFs involved in the neuronal injury response and suggested that their activity in injured DRG neurons might be regulated at the post-transcriptional level. These findings led the authors to test the interaction between activated TFs identified in the computational analysis and the retrograde motor dynein. They found 11 TFs whose association with dynein differed between injured and naive nerves. Five TFs STAT3Figure 1 Injury-induced STAT3 axonal translation and retrograde transport promotes sensory neurons survival. Following the peripheral nerve injury, Ca 2 þ influx activates STAT3 local protein synthesis. The newly synthesized STAT3 is phosphorylated and binds to the retrograde molecular motor dynein via the nuclear import factor importin a5. Retrograde transport of the STAT3 injury signal complex back to the DRG cell body activates the transcription of target genes to induce a survival program. Whether STAT3 expression and activation in DRG cell body plays a similar or distinct role following the injury remains to be determined.

Sorting nexin 3 induces myocardial injury via promoting retromer-dependent nuclear trafficking of STAT3

“…Importin α3 (also called as Kpna3), a nuclear import factor, is responsible for STAT3 nuclear import independent of tyrosine phosphorylation 21,22 . Upon axons injury exposure, the newly-synthesized STAT3 combined with importin α5 and dynein (a retrograde molecular motor), and transported back to the cell body [23][24][25] . STAT3 co-localizes with endocytic vesicles in transit from the cell membrane to the perinuclear region, the perinuclear endosomal compartment to sustain phosphorylated STAT3 (Y705) in nucleus [26][27][28][29] .…”