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Nonsense-mediated decay constrains nociceptive responses through repression of the integrated stress response

ABSTRACT: RNA stability is meticulously controlled. Here, we sought to determine if an essential post-transcriptional regulatory mechanism plays a role in pain. Nonsense-mediated decay (NMD ) safeguards against translation of mRNAs that harbor premature termination codons and controls the stability of roughly 10% of typical protein-coding mRNAs. It hinges on the activity of the conserved kinase SMG1. Both SMG1 and its target UPF1 are expressed in sensory neurons throughout the dorsal root ganglion (DRG). SMG1 protein is present in DRG neurons and their fibers in the sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. Among the characteristics of NMD substrates, the most prominent is structure specifically in the 3′UTR. We confirmed multiple NMD stability targets in sensory neurons including ATF4. AFT4 is preferentially translated during the integrated stress response (ISR). This led us to ask if suspension of NMD induces the ISR. Indeed, blockade of NMD increases eIF2-alpha phosphorylation, a key marker of the integrated stress response. Next, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 result in mechanical hypersensitivity that persists for several days and priming to a subthreshold dose of PGE2. Priming was fully rescued by a small molecule inhibitor of the ISR. Collectively, our results indicate that suspension of NMD promotes pain through activation of the ISR.

ORGANISM(S): Mus musculus

PROVIDER: GSE211127 | GEO | 2023/05/01

REPOSITORIES: GEO

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