Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced cultured human muscle fibers
Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced cultured human muscle fibers
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DOI：
10.1111/j.1471-4159.2006.03668.x
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Askanas, V
中科院分区：
文献类型：
--
作者：
Nogalska, A;Engel, WK;Askanas, V
Herp 是一种位于内质网 (ER) 膜中的应激反应蛋白。 Herp 被认为可以改善 ER 折叠、减少 ER 蛋白负载并参与 ER 相关降解 (ERAD)。肌纤维内泛素化多蛋白聚集体含有淀粉样蛋白 - β (A beta) 或磷酸化 tau 蛋白等，是散发性包涵体肌炎 (s-IBM) 的特征。 ER 应激和蛋白酶体抑制似乎在 s-IBM 发病机制中发挥作用。我们现在已经研究了 s-IBM 肌纤维和 ER 应激诱导或蛋白酶体抑制的培养人类肌纤维中的 Herp。在 s-IBM 肌纤维中： (i) Herp 以聚集体的形式具有强烈的免疫反应性，与 A beta、GRP78 和 β2 蛋白酶体亚基共定位； (ii) Herp mRNA 和蛋白质增加。在内质网应激诱导的培养人肌纤维中： (i) Herp 免疫反应性广泛增加； (ii) Herp mRNA 和蛋白质增加。在蛋白酶体抑制的培养人肌纤维中：（i）疱疹病毒免疫反应性呈聚集体形式； (ii) Herp 蛋白增加，但其 mRNA 没有增加。因此，在 s-IBM 肌纤维中： (i) Herp 的增加可能是由于 ER 应激和蛋白酶体抑制所致； (ii) Herp 与 Aβ、蛋白酶体和 ER 伴侣 GRP78 的共定位可以反映其在 ER 中细胞毒性蛋白的加工和降解中的可能作用。
Herp is a stress-response protein localized in the endoplasmic reticulum (ER) membrane. Herp was proposed to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD). Intra-muscle-fiber ubiquitinated multiprotein-aggregates containing, among other proteins, either amyloid-beta (A beta) or phosphorylated tau are characteristic of sporadic inclusion-body myositis (s-IBM). ER stress and proteasome inhibition appear to play a role in s-IBM pathogenesis. We have now studied Herp in s-IBM muscle fibers and in ER-stress-induced or proteasome-inhibited cultured human muscle fibers. In s-IBM muscle fibers: (i) Herp was strongly immunoreactive in the form of aggregates, which co-localized with A beta, GRP78, and beta 2 proteasome subunit; (ii) Herp mRNA and protein were increased. In ER-stress-induced cultured human muscle fibers: (i) Herp immunoreactivity was diffusely increased; (ii) Herp mRNA and protein were increased. In proteasome-inhibited cultured human muscle fibers: (i) Herp immunoreactivity was in the form of aggregates; (ii) Herp protein was increased, but its mRNA was not. Accordingly, in s-IBM muscle fibers: (i) increase of Herp might be due to both ER-stress and proteasome inhibition; (ii) co-localization of Herp with A beta, proteasome, and ER-chaperone GRP78 could reflect its possible role in processing and degradation of cytotoxic proteins in ER.