The role of p62/SQSTM1 in sporadic inclusion body myositis
The role of p62/SQSTM1 in sporadic inclusion body myositis
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DOI：
10.1016/j.nmd.2016.12.009
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发表时间：
2017-04-01
影响因子：
2.8
通讯作者：
Kusaka, Hirofumi
中科院分区：
文献类型：
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作者：
Nakano, Satoshi;Oki, Mitsuaki;Kusaka, Hirofumi
我们检查了散发性包涵体肌炎 (s-IBM) 患者中针对泛素化蛋白聚集体的选择性自噬。自噬的形式需要 p62/SQSTM1 中丝氨酸 403 的磷酸化，以与 Lys63 连接的泛素结合，以及 p62 泛素化蛋白缀合物与 LC3 的结合。在 16 名 s-IBM 患者的肌肉活检标本中，我们在双色免疫荧光显微镜下比较了 p62 (aa120-440) 与 1) Ser403 磷酸化 p62 (S403-pp62)、2) Lys63 连接的泛素和 3) LC3 的分布。 S403-pp62、Lys63 连接的泛素和 LC3 与 p62 聚集体共定位，分别为 79.05% +/- 13.64%（平均值 +/- SD）、66.54% +/- 19.91% 和 51.84% +/- 14.1%。尽管在 p62 聚集体中总是观察到 S403-pp62 和 Lys63 连接的泛素的阳性沉积，但 LC3 经常表现出与 p62 分离的分布。我们还发现含有大量 p62 阳性小点的纤维，这些点对所有三种标记物均呈阴性，并且在肌炎对照中也观察到。结果表明，s-IBM中的p62、Lys63连接的泛素和LC3联合执行选择性自噬。 p62 可以由所有类型肌炎中的一些细胞应激诱导；然而，在 s-IBM 中，p62 泛素化蛋白复合物与 LC3 的结合受损可能会在初始阶段停止自噬过程，从而导致 p62 寡聚体与 Lys63 泛素化蛋白形成聚集体。 (C) 2017 Elsevier B.V. 保留所有权利。
We examined selective autophagy against ubiquitinated protein aggregates in sporadic inclusion body myositis (s-IBM) patients. The form of autophagy requires phosphorylation of serine 403 in p62/SQSTM1 to bind to Lys63-linked ubiquitin and the binding of the p62-ubiquitinated protein conjugates to LC3. In muscle biopsy specimens from 16 s-IBM patients, we compared the distribution of p62 (aa120-440) with 1) Ser403-phosphorylated p62 (S403-pp62), 2) Lys63-linked ubiquitin and 3) LC3 in double-colour immunofluorescence microscopy. S403-pp62, Lys63-linked ubiquitin and LC3 colocalised with p62 aggregates, 79.05% +/- 13.64% (mean +/- SD), 66.54% +/- 19.91% and 51.84% +/- 14.1%, respectively. Although positive deposits of S403-pp62 arid Lys63-linked ubiquitin were always observed within p62 aggregates, LC3 often showed dissociated distribution from p62. We also found fibres containing small, numerous p62-positive dots that were negative for all three markers and were also observed in myositis controls. The results indicate that p62, Lys63-linked ubiquitin and LC3 in s-IBM join to perform selective autophagy. p62 could be induced by some cellular stresses in all types of myositis; however, in s-IBM, compromised binding of the p62ubiquitinated protein complex to LC3 could stop the autophagy process in its initial stages, which causes the formation of aggregates of p62-oligomers with Lys63-ubiquitinated proteins. (C) 2017 Elsevier B.V. All rights reserved.