Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Nucleic Acids Res. 2023 Feb 22;51(3):1245-1259. doi: 10.1093/nar/gkac1219.
Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while the inclusion of Mbnl2 exon 9 shifts the reading frame to an alternative C-terminus. We show that the C-terminus lacking exon 9 contains a PEST domain which causes proteasomal degradation. Loss of MBNL1 increases the inclusion of exon 9, resulting in an alternative C-terminus lacking the PEST domain and the increase of MBNL2. We further find that the compensatory mechanism is active in a mouse DM1 model. Together, this study uncovers the compensatory mechanism by which loss of MBNL1 upregulates its paralog MBNL2 and highlights a potential role of the compensatory mechanism in DM1.
基因功能的丧失可以通过具有冗余功能的旁系同源物来补偿。肌营养不良症 1 型（DM1）中 RNA 结合蛋白的 Muscleblind-Like（MBNL）家族的旁系同源物就是这种补偿的一个例子，它们被隔离并失去功能。MBNL1 的缺失会增加其低表达组织中 MBNL2 的水平，从而使 MBNL2 能够在功能上补偿 MBNL1 的缺失。在这里，我们表明 MBNL1 的缺失会增加 Mbnl2 外显子 6 和外显子 9 的包含。我们发现 Mbnl2 外显子 6 的包含会增加 MBNL2 向核内的易位，而 Mbnl2 外显子 9 的包含会将阅读框转移到另一个 C 末端。我们表明，缺乏外显子 9 的 C 末端含有 PEST 结构域，会导致蛋白酶体降解。MBNL1 的缺失会增加外显子 9 的包含，从而产生缺乏 PEST 结构域的替代 C 末端和 MBNL2 的增加。我们进一步发现，补偿机制在 DM1 的小鼠模型中是活跃的。总之，这项研究揭示了 MBNL1 缺失上调其旁系同源物 MBNL2 的补偿机制，并强调了补偿机制在 DM1 中的潜在作用。
