Ribosome profiling reveals that post-transcriptional control of Nalf1 by heterogeneous nuclear ribonucleoprotein L is required for paclitaxel-induced neuropathic pain.

abstractSensory neurons are integral to the genesis and maintenance of neuropathic pain. The molecular mechanisms that mediate long-lived changes in their excitability are unclear. Here, we leverage functional genomics approaches to survey changes in RNA abundance and translation in dorsal root ganglion neurons from a mouse model of paclitaxel-induced neuropathic pain. We focus specifically on females as paclitaxel is a first-line therapy for breast cancer. The sequencing data indicate that substantially more changes occur at the level of translation (n = 404) than transcription and decay (n = 109). We discovered that a core subunit of the sodium leak channel (NALCN) channel, auxiliary factor 1 (NALF1), is preferentially translated in response to paclitaxel. This effect is mediated by the RNA-binding protein heterogeneous nuclear ribonucleoprotein L (HNRNP L). Heterogeneous nuclear ribonucleoprotein L binds a 14 base CA-rich element (CARE) in the Nalf1 3' untranslated region (3'UTR). Genetic elimination of either HNRNP L, the Nalf1 CARE motif, or the pore-forming subunit of the nonselective NALCN diminishes pain amplification in vivo. Collectively, these results illustrate that an element situated in a 3'UTR is required for neuropathic pain in female mice.