Trisomy 21 increases microtubules and disrupts centriolar satellite localization.
Trisomy 21 increases microtubules and disrupts centriolar satellite localization.
复制标题
21三体增加微管，破坏向心卫星定位。
DOI：
10.1091/mbc.e21-10-0517-t
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发表时间：
2022-07-01
影响因子：
3.3
通讯作者：
Pearson, Chad G.
中科院分区：
文献类型：
--
作者：
McCurdy, Bailey L.;Jewett, Cayla E.;Stemm-Wolf, Alexander J.;Huy Nguyen Duc;Joshi, Molishree;Espinosa, Joaquin M.;Prekeris, Rytis;Pearson, Chad G.
21三体是唐氏综合征的来源，导致21号染色体常驻基因Pericentrin（PCNT）蛋白质增加0.5倍，并减少初级纤毛形成和信号传导。我们调查PCNT失衡如何破坏纤毛。使用21号染色体剂量增加的同基因RPE-1细胞，我们发现PCNT聚集在中心体周围，作为一簇扩大的细胞质斑点，定位于沿着微管（MT）和MT末端。细胞质PCNT点影响初级纤毛所需的MT运输网络的密度、稳定性和定位。PCNT斑点似乎隔离货物周边的中心体，我们称之为pericentrosomal拥挤。中心粒卫星蛋白PCM 1，CEP 131和CEP 290，纤毛发生的重要，积累在扩大PCNT斑点在三体21细胞。当21号染色体倍性升高时，减少PCNT足以减少PCNT斑点和中心体周围拥挤，重新建立中心体周围正常密度的MT，并将纤毛发生恢复到野生型水平。一个短暂的减少MT也减少了pericentrosomal拥挤和部分救援纤毛发生在三体21细胞，表明PCNT增加导致MT网络的缺陷，有害于正常的中心粒卫星分布。我们建议，21号染色体非整倍性破坏MT依赖的细胞内运输所需的初级纤毛。
Trisomy 21, the source of Down syndrome, causes a 0.5-fold protein increase of the chromosome 21-resident gene Pericentrin (PCNT) and reduces primary cilia formation and signaling. We investigate how PCNT imbalances disrupt cilia. Using isogenic RPE-1 cells with increased chromosome 21 dosage, we find PCNT accumulates around the centrosome as a cluster of enlarged cytoplasmic puncta that localize along microtubules (MTs) and at MT ends. Cytoplasmic PCNT puncta impact the density, stability, and localization of the MT trafficking network required for primary cilia. The PCNT puncta appear to sequester cargo peripheral to centrosomes in what we call pericentrosomal crowding. The centriolar satellite proteins PCM1, CEP131, and CEP290, important for ciliogenesis, accumulate at enlarged PCNT puncta in trisomy 21 cells. Reducing PCNT when chromosome 21 ploidy is elevated is sufficient to decrease PCNT puncta and pericentrosomal crowding, reestablish a normal density of MTs around the centrosome, and restore ciliogenesis to wild-type levels. A transient reduction in MTs also decreases pericentrosomal crowding and partially rescues ciliogenesis in trisomy 21 cells, indicating that increased PCNT leads to defects in the MT network deleterious to normal centriolar satellite distribution. We propose that chromosome 21 aneuploidy disrupts MT-dependent intracellular trafficking required for primary cilia.