Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
Sci Rep. 2022 Feb 10;12(1):2306. doi: 10.1038/s41598-022-06135-5.
Myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), regulates the expression of many cytoskeletal genes in response to cytoplasmic and nuclear actin dynamics. Here we describe a novel mechanism to regulate MRTF-A activity within the nucleus by showing that lamina-associated polypeptide 2α (Lap2α), the nucleoplasmic isoform of Lap2, is a direct binding partner of MRTF-A, and required for the efficient expression of MRTF-A/SRF target genes. Mechanistically, Lap2α is not required for MRTF-A nuclear localization, unlike most other MRTF-A regulators, but is required for efficient recruitment of MRTF-A to its target genes. This regulatory step takes place prior to MRTF-A chromatin binding, because Lap2α neither interacts with, nor specifically influences active histone marks on MRTF-A/SRF target genes. Phenotypically, Lap2α is required for serum-induced cell migration, and deregulated MRTF-A activity may also contribute to muscle and proliferation phenotypes associated with loss of Lap2α. Our studies therefore add another regulatory layer to the control of MRTF-A-SRF-mediated gene expression, and broaden the role of Lap2α in transcriptional regulation.
肌球蛋白相关转录因子 A（MRTF-A）是血清反应因子（SRF）的共激活因子，可调节细胞骨架基因的表达，以响应细胞质和核中的肌动蛋白动态变化。在这里，我们通过显示核纤层相关蛋白 2α（Lap2α），即 Lap2 的核质同工型，是 MRTF-A 的直接结合伴侣，并需要有效地表达 MRTF-A/SRF 靶基因，来描述一种在核内调节 MRTF-A 活性的新机制。从机制上讲，不像大多数其他 MRTF-A 调节剂那样，Lap2α 不要求 MRTF-A 的核定位，但需要有效地将 MRTF-A 募集到其靶基因上。此调节步骤发生在 MRTF-A 染色质结合之前，因为 Lap2α 既不与 MRTF-A/SRF 靶基因上的活性组蛋白标记相互作用，也不特别影响这些标记。表型上，Lap2α 是血清诱导的细胞迁移所必需的，并且失调的 MRTF-A 活性也可能导致与 Lap2α 缺失相关的肌肉和增殖表型。因此，我们的研究为 MRTF-A-SRF 介导的基因表达的控制增加了另一个调节层，并拓宽了 Lap2α 在转录调控中的作用。
