HuR Mediates Changes in the Stability of AChR β-Subunit mRNAs after Skeletal Muscle Denervation.

摘要: Acetylcholine receptors (AChRs) are heteromeric membrane proteins essential for neurotransmission at the neuromuscular junction. Previous work showed that muscle denervation increases expression of AChR mRNAs due to transcriptional activation subunit genes. However, it remains possible post-transcriptional mechanisms also involved in controlling levels following denervation. We examined whether events indeed regulate β-subunit response First, vitro stability assays revealed half-life was increased presence denervated protein extracts. A bioinformatics analysis existence a conserved AU-rich element (ARE) 3′-untranslated region (UTR) mRNA. Furthermore, mouse injected with luciferase reporter construct containing 3′UTR, caused an increase activity. By contrast, mutation this ARE prevented increase. observed RNA-binding human antigen R (HuR) and induced its translocation cytoplasm. Importantly, HuR binds endogenous transcripts cultured myotubes vivo, binding is versus innervated muscles. Finally, p38 MAPK, pathway known activate HuR, as result MKK3/6 decrease MKP-1 expression, thereby leading transcripts. Together, these results demonstrate important contribution regulating point toward central role mediating synaptic gene expression. SIGNIFICANCE STATEMENT Muscle convenient model examine genes encoding junction, especially acetylcholine (AChRs). Despite accepted regulation, which implicates mechanisms, plausible such cannot fully account changes show turn, causes muscle. Our findings first time skeletal muscle, points development while paving way developing RNA-based therapeutics diseases.