Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Am J Pathol. 2014 Apr;184(4):1119-1131. doi: 10.1016/j.ajpath.2013.12.011. Epub 2014 Jan 30.
Alanine expansion mutations in poly(A)-binding protein nuclear 1 (PABPN1) cause muscle weakness in the late-onset disorder oculopharyngeal muscular dystrophy. In affected muscles, expanded PABPN1 forms nuclear aggregates, depleting levels of soluble PABPN1 and inducing a genome-wide shift from distal to proximal polyadenylation site usage. PABPN1 protein accumulation is regulated by the ubiquitin proteasome system, which is highly dysregulated in oculopharyngeal muscular dystrophy. We show that ARIH2 E3-ligase regulates PABPN1 protein accumulation and aggregation. Levels of ARIH2 mRNA are regulated by PABPN1 via proximal polyadenylation site usage. We demonstrate that masking the proximal polyadenylation site in ARIH2 3' untranslated region by antisense oligonucleotides elevates the expression of ARIH2 and PABPN1 and restores myogenic defects that are induced by ARIH2 or PABPN1 down-regulation in cell culture. In vivo ARIH2 mRNA levels significantly decrease from midlife in vastus lateralis muscles and highly correlate with muscle degeneration. We suggest that the expression of both genes is maintained by a feed-forward loop between mRNA stability regulated by PABPN1 and protein turnover regulated by ARIH2.
精氨酸扩展突变多聚（A）结合蛋白核 1（PABPN1）导致晚发性眼咽型肌营养不良症的肌肉无力。在受影响的肌肉中，扩展的 PABPN1 形成核聚集体，耗尽可溶性 PABPN1 的水平，并诱导从远端到近端聚腺苷酸化位点使用的全基因组转移。PABPN1 蛋白积累受泛素蛋白酶体系统调节，该系统在眼咽型肌营养不良症中高度失调。我们表明 ARIH2 E3 连接酶调节 PABPN1 蛋白积累和聚集。ARIH2 mRNA 水平通过近端聚腺苷酸化位点使用受 PABPN1 调节。我们证明，通过反义寡核苷酸掩盖 ARIH2 3'非翻译区中的近端聚腺苷酸化位点，可提高 ARIH2 和 PABPN1 的表达，并恢复由 ARIH2 或 PABPN1 在细胞培养中下调诱导的成肌缺陷。在体内，从股外侧肌的中年开始，ARIH2 mRNA 水平显著降低，并且与肌肉退化高度相关。我们认为这两个基因的表达通过由 PABPN1 调节的 mRNA 稳定性和由 ARIH2 调节的蛋白周转之间的正反馈环来维持。
