ERK1/2 Phosphorylation of FHOD Connects Signaling and Nuclear Positioning Alternations in Cardiac Laminopathy
ERK1/2 Phosphorylation of FHOD Connects Signaling and Nuclear Positioning Alternations in Cardiac Laminopathy
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DOI：
10.1016/j.devcel.2019.10.023
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发表时间：
2019-12-02
影响因子：
11.8
通讯作者：
Gundersen, Gregg G.
中科院分区：
文献类型：
--
作者：
Antoku, Susumu;Wu, Wei;Gundersen, Gregg G.
核纤层蛋白A/C基因（LMNA）的突变会导致心肌病，也会破坏成纤维细胞的核定位。导致心肌病的LMNA突变提高了心脏中的ERK 1/2活性，并且抑制ERK 1/2激酶活性可改善病理，但下游效应物在很大程度上仍然未知。我们现在表明，来自Lmna突变和心脏ERK 1/2活性升高的小鼠的心肌细胞改变了核定位。在成纤维细胞中，ERK 1/2激活通过磷酸化FHOD 1的S498负调节核运动。非磷酸化FHOD 1变体的表达挽救了表达心肌病引起的核纤层蛋白A突变体的成纤维细胞的核运动缺陷。在患有LMNA突变诱导的心肌病的小鼠心脏中，ERK 1/2介导FHOD 3的磷酸化，FHOD 3是一种在心脏组织中高度表达的同种型。FHOD 1和FHOD 3的磷酸化抑制其肌动蛋白成束活性。这些结果表明，ERK 1/2对FHOD蛋白的磷酸化是核定位的关键开关，并可能在LMNA突变引起的心肌病的发病机制中发挥作用。
Mutations in the lamin A/C gene (LMNA) cause cardiomyopathy and also disrupt nuclear positioning in fibroblasts. LMNA mutations causing cardiomyopathy elevate ERK1/2 activity in the heart, and inhibition of the ERK1/2 kinase activity ameliorates pathology, but the downstream effectors remain largely unknown. We now show that cardiomyocytes from mice with an Lmna mutation and elevated cardiac ERK1/2 activity have altered nuclear positioning. In fibroblasts, ERK1/2 activation negatively regulated nuclear movement by phosphorylating S498 of FHOD1. Expression of an unphosphorylatable FHOD1 variant rescued the nuclear movement defect in fibroblasts expressing a cardiomyopathy-causing lamin A mutant. In hearts of mice with LMNA mutation-induced cardiomyopathy, ERK1/2 mediated phosphorylation of FHOD3, an isoform highly expressed in cardiac tissue. Phosphorylation of FHOD1 and FHOD3 inhibited their actin bundling activity. These results show that phosphorylation of FHOD proteins by ERK1/2 is a critical switch for nuclear positioning and may play a role in the pathogenesis of cardiomyopathy caused by LMNA mutations.