BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes
BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes
复制标题
与肌病和神经病相关的BAG3 Pro209突变体将CASA复合体的伴侣重新定位到侵袭体
DOI：
10.1038/s41598-020-65664-z
复制
发表时间：
2020-05-29
影响因子：
4.6
通讯作者：
Timmerman, Vincent
中科院分区：
文献类型：
--
作者：
Adriaenssens, Elias;Tedesco, Barbara;Timmerman, Vincent
三个错义突变针对共同伴侣Bcl2相关的athanogene 3(BAG3)中相同的Pro 209(Pro209)密码子，已被报道可导致远端肌病、扩张型心肌病或Charcot-Marie-Tooth 2型神经病。然而，目前尚不清楚在BAG3中携带这三个杂合子Pro209突变的罕见患者的不同临床谱系是否存在不同的分子机制。在这里，我们研究了所有这三个变体，并将它们与导致扩张型心肌病的BAG3_Glu455Lys突变进行了比较。我们发现所有的BAG3_Pro209突变体都获得了一种有毒的功能增益，这导致这些突变体以不可溶的HDAC6和Vimentin阳性侵袭体的形式积累。突变体BAG3形成的侵袭体导致HSPB8和HSP70等其他伴侣蛋白的重新定位，它们与BAG3一起促进了所谓的伴侣辅助选择性自噬(CASA)。由于它们更倾向于聚集，突变的BAG3将泛素化的客户蛋白捕获在侵袭体上，阻止了它们的有效清除。综上所述，这些数据表明，所有BAG3_Pro209突变体，无论其不同的临床表型，都具有导致蛋白质稳态逐渐丧失的功能获得的特征。
Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2-associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6- and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 led to a relocation of other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so-called chaperone-assisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis.