TY - JOUR
T1 - Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response
AU - De La Peña, June Bryan
AU - Chase, Rebecca
AU - Kunder, Nikesh
AU - Smith, Patrick R.
AU - Lou, Tzu Fang
AU - Stanowick, Alexander
AU - Suresh, Prarthana
AU - Shukla, Tarjani
AU - Butcher, Samuel E.
AU - Price, Theodore J.
AU - Campbell, Zachary T.
N1 - Publisher Copyright:
Copyright © 2023 the authors.
PY - 2023/4/19
Y1 - 2023/4/19
N2 - RNA stability is meticulously controlled. Here, we sought to determine whether 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 ∼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 murine DRG sensory neurons. SMG1 protein is present in both the DRG and sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. We confirmed multiple NMD stability targets in sensory neurons, including ATF4. ATF4 is preferentially translated during the integrated stress response (ISR). This led us to ask whether suspension of NMD induces the ISR. Inhibition of NMD increased eIF2-a phosphorylation and reduced the abundance of the eIF2-a phosphatase constitutive repressor of eIF2-a phosphorylation. Finally, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 results in mechanical hypersensitivity in males and females 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 stimulation of the ISR.
AB - RNA stability is meticulously controlled. Here, we sought to determine whether 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 ∼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 murine DRG sensory neurons. SMG1 protein is present in both the DRG and sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. We confirmed multiple NMD stability targets in sensory neurons, including ATF4. ATF4 is preferentially translated during the integrated stress response (ISR). This led us to ask whether suspension of NMD induces the ISR. Inhibition of NMD increased eIF2-a phosphorylation and reduced the abundance of the eIF2-a phosphatase constitutive repressor of eIF2-a phosphorylation. Finally, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 results in mechanical hypersensitivity in males and females 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 stimulation of the ISR.
KW - integrated stress response
KW - nociception
KW - nonsense-mediated decay
KW - pain
KW - priming
UR - http://www.scopus.com/inward/record.url?scp=85153119844&partnerID=8YFLogxK
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U2 - 10.1523/JNEUROSCI.1604-22.2023
DO - 10.1523/JNEUROSCI.1604-22.2023
M3 - Article
C2 - 36894318
AN - SCOPUS:85153119844
SN - 0270-6474
VL - 43
SP - 2921
EP - 2933
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 16
ER -