Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion.
Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion.
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DOI：
10.1016/j.yjmcc.2018.07.248
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发表时间：
2018-08
影响因子：
5
通讯作者：
Gehmlich K
中科院分区：
文献类型：
--
作者：
Ehsan M;Kelly M;Hooper C;Yavari A;Beglov J;Bellahcene M;Ghataorhe K;Poloni G;Goel A;Kyriakou T;Fleischanderl K;Ehler E;Makeyev E;Lange S;Ashrafian H;Redwood C;Davies B;Watkins H;Gehmlich K
富含半胱氨酸和甘氨酸的蛋白质3（CSRP 3）编码肌肉LIM蛋白质（MLP），其是肥厚性心肌病（HCM）的一种公认的疾病基因。MLP与其他公认的HCM疾病基因编码的蛋白质相反，是非肌节的，并且在心肌细胞中具有重要的信号传导功能。为了深入了解所涉及的疾病机制，我们建立了一个基因敲入小鼠（KI）模型，该模型携带有充分记录的导致HCM的CSRP 3突变C58 G。纯合子KI/KI小鼠的体内表型分析显示了一种稳健的心肌病表型，伴有舒张期和收缩期左心室功能障碍，这得到了心脏重量测量值增加的支持。通过RNA-seq的转录组分析鉴定了这些心脏中促纤维化信号传导的激活、胎儿基因程序的诱导和肥大信号传导标志物的激活。进一步的体外分析证实了这些途径在转录物和蛋白质水平上的激活。有趣的是，MLP的丰度在KI/KI小鼠中减少了80%，在KI/+小鼠中减少了50%。在细胞研究中还观察到另外两种引起HCM的CSRP 3突变（L44 P和S54 R/E55 G）的蛋白质消耗。我们表明，MLP耗尽是由蛋白酶体的行动。此外，MLP C58 G与Bag 3相互作用，并在纯合敲入小鼠中导致蛋白毒性反应，如Bag 3和相关热休克蛋白的诱导所示。总之，新产生的小鼠模型提供了对由非肌节蛋白MLP突变引起的心肌病的潜在疾病机制的见解。此外，我们的细胞实验表明，蛋白质消耗和蛋白酶体过载也在我们研究的其他HCM引起的CSPR 3突变中发挥作用，表明功能性MLP水平降低可能是HCM引起的CSPR 3突变的常见机制。我们提出了一种非肉瘤肥厚型心肌病（HCM）的小鼠模型。纯合子肌肉LIM蛋白（MLP）C58 G小鼠具有收缩和舒张功能障碍。MLP C58 G通过蛋白酶体途径耗尽。蛋白质消耗也是进一步HCM导致MLP突变的标志。MLP C58 G与Bag 3相互作用并引起蛋白毒性反应。
Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations. We present a mouse model for non-sarcomeric hypertrophic cardiomyopathy (HCM). Homozygous Muscle LIM Protein (MLP) C58G mice have systolic and diastolic dysfunction. MLP C58G is depleted via proteasomal pathways. Protein depletion is also a hallmark of further HCM causing MLP mutations. MLP C58G interacts with Bag3 and causes a proteotoxic response.
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影响因子：
5
作者：
Liu Q;Molkentin JD
通讯作者：
Molkentin JD
影响因子：
64.5
作者：
Knöll, R;Hoshijima, M;Chien, KR
通讯作者：
Chien, KR
影响因子：
5
作者：
Feldman AM;Gordon J;Wang J;Song J;Zhang XQ;Myers VD;Tilley DG;Gao E;Hoffman NE;Tomar D;Madesh M;Rabinowitz J;Koch WJ;Su F;Khalili K;Cheung JY
通讯作者：
Cheung JY
影响因子：
3.5
作者：
Geier, Christian;Gehmlich, Katja;Oezcelik, Cemil
通讯作者：
Oezcelik, Cemil
影响因子：
46.9
作者：
Lindsten, K;Menéndez-Benito, V;Dantuma, NP
通讯作者：
Dantuma, NP