Imbalances in protein homeostasis caused by mutant desmin
Imbalances in protein homeostasis caused by mutant desmin
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结蛋白突变引起的蛋白质稳态失衡
DOI：
10.1111/nan.12516
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发表时间：
2019
影响因子：
5
通讯作者：
Schröder R
中科院分区：
文献类型：
--
作者：
Winter L;Unger A;Berwanger C;Spörrer M;Türk M;Chevessier F;Strucksberg KH;Schlötzer- Schrehard U;Wittig I;Goldmann WH;Marcus K;Linke WA;Clemen CS;Schröder R
目的我们研究了新产生的永生化杂合和纯合R349 P结蛋白敲入成肌细胞，并结合相应的结蛋白病小鼠作为结蛋白病模型，以分析响应R349 P突变结蛋白存在的主要蛋白质质量控制过程。结蛋白敲入骨骼肌成肌细胞和肌管。通过间接免疫荧光显微镜、蛋白酶体活性测量和免疫印迹法研究骨骼肌切片和培养的肌细胞，以确定自噬率、分子伴侣辅助的选择性自噬和热休克蛋白水平。肌肉切片进行了进一步分析，通过透射和免疫金电子microscopic.ResultsWe表明，突变结蛋白（一）增加蛋白酶体的活性，（二）刺激macroautophagy，（三）失调的分子伴侣辅助选择性自噬和（四）提高αB-晶体蛋白和HSP 27的蛋白质水平。αB-晶体蛋白和热休克蛋白27以及热休克蛋白90显示易位模式，从Z-光盘以及Z-I路口，分别在显性和隐性desminopathies.ConclusionsOur研究结果表明，存在的R349 P突变结蛋白导致骨骼肌蛋白质稳态通过异常活动的所有主要蛋白质质量控制系统的一般失衡。这些系统的活性增强和必需热休克蛋白的亚细胞转移可能有害地促进了先前观察到的结蛋白本身和结蛋白结合伴侣的周转增加，这在结蛋白病的发展过程中触发了肌节外细胞骨架和肌原纤维装置的进行性功能障碍。
AimsWe investigated newly generated immortalized heterozygous and homozygous R349P desmin knock‐in myoblasts in conjunction with the corresponding desminopathy mice as models for desminopathies to analyse major protein quality control processes in response to the presence of R349P mutant desmin.MethodsWe used hetero‐ and homozygous R349P desmin knock‐in mice for analyses and for crossbreeding with p53 knock‐out mice to generate immortalized R349P desmin knock‐in skeletal muscle myoblasts and myotubes. Skeletal muscle sections and cultured muscle cells were investigated by indirect immunofluorescence microscopy, proteasomal activity measurements and immunoblotting addressing autophagy rate, chaperone‐assisted selective autophagy and heat shock protein levels. Muscle sections were further analysed by transmission and immunogold electron microscopy.ResultsWe demonstrate that mutant desmin (i) increases proteasomal activity, (ii) stimulates macroautophagy, (iii) dysregulates the chaperone assisted selective autophagy and (iv) elevates the protein levels of αB‐crystallin and Hsp27. Both αB‐crystallin and Hsp27 as well as Hsp90 displayed translocation patterns from Z‐discs as well as Z‐I junctions, respectively, to the level of sarcomeric I‐bands in dominant and recessive desminopathies.ConclusionsOur findings demonstrate that the presence of R349P mutant desmin causes a general imbalance in skeletal muscle protein homeostasis via aberrant activity of all major protein quality control systems. The augmented activity of these systems and the subcellular shift of essential heat shock proteins may deleteriously contribute to the previously observed increased turnover of desmin itself and desmin‐binding partners, which triggers progressive dysfunction of the extrasarcomeric cytoskeleton and the myofibrillar apparatus in the course of the development of desminopathies.
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影响因子：
4.6
作者：
Diermeier S;Iberl J;Vetter K;Haug M;Pollmann C;Reischl B;Buttgereit A;Schürmann S;Spörrer M;Goldmann WH;Fabry B;Elhamine F;Stehle R;Pfitzer G;Winter L;Clemen CS;Herrmann H;Schröder R;Friedrich O
通讯作者：
Friedrich O
影响因子：
12.7
作者：
Winter L;Wittig I;Peeva V;Eggers B;Heidler J;Chevessier F;Kley RA;Barkovits K;Strecker V;Berwanger C;Herrmann H;Marcus K;Kornblum C;Kunz WS;Schröder R;Clemen CS
通讯作者：
Clemen CS
影响因子：
7.5
作者：
Yu S;Melia TJ
通讯作者：
Melia TJ
影响因子：
3.3
作者：
Mizushima, N;Yamamoto, A;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
3.7
作者：
Tucker NR;Shelden EA
通讯作者：
Shelden EA