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  • The RNA-Binding Protein HuR Is Integral to the Function of Nociceptors in Mice and Humans.

The RNA-Binding Protein HuR Is Integral to the Function of Nociceptors in Mice and Humans.

The Journal of neuroscience : the official journal of the Society for Neuroscience (2022-10-22)
Nikesh Kunder, June Bryan de la Peña, Tzu-Fang Lou, Rebecca Chase, Prarthana Suresh, Jennifer Lawson, Tarjani Shukla, Bryan Black, Zachary T Campbell
ABSTRACT

HuR is an RNA-binding protein implicated in RNA processing, stability, and translation. Previously, we examined protein synthesis in dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We found that the HuR consensus binding element was enriched in transcripts with elevated translation. HuR is expressed in the soma of nociceptors and their axons. Pharmacologic inhibition of HuR with the small molecule CMLD-2 reduced the activity of mouse and human sensory neurons. Peripheral administration of CMLD-2 in the paw or genetic elimination of HuR from sensory neurons diminished behavioral responses associated with NGF- and IL-6-induced allodynia in male and female mice. Genetic disruption of HuR altered the proximity of mRNA decay factors near a key neurotrophic factor (TrkA). Collectively, the data suggest that HuR is required for local control of mRNA stability and reveals a new biological function for a broadly conserved post-transcriptional regulatory factor.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in excitability, which may contribute to chronic pain. Noxious cues that promote pain lead to rapid induction of protein synthesis. The underlying mechanisms that confer specificity to mRNA control in nociceptors are unclear. Here, we identify a conserved RNA-binding protein called HuR as a key regulatory factor in sensory neurons. Using a combination of genetics and pharmacology, we demonstrate that HuR is required for signaling in nociceptors. In doing so, we report an important mechanism of mRNA control in sensory neurons that ensures appropriate nociceptive responses to inflammatory mediators.

MATERIALS
Product Number
Brand
Product Description

Roche
Trypsin Inhibitor, from chicken egg white
Roche
Papain, from Carica papaya
Sigma-Aldrich
Anti-TrkA Antibody, Upstate®, from rabbit
Sigma-Aldrich
Anti-Neurofilament 200 antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution