Involvement of endoplasmic reticulum stress in hereditary tyrosinemia type I
Involvement of endoplasmic reticulum stress in hereditary tyrosinemia type I
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DOI：
10.1074/jbc.m506804200
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发表时间：
2006-03-03
影响因子：
4.8
通讯作者：
Tanguay, RM
中科院分区：
文献类型：
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作者：
Bergeron, A;Jorquera, R;Tanguay, RM
遗传性I型酪氨酸血症（HTI）是酪氨酸降解途径中最严重的疾病。HTI是由富马酰乙酸水解酶（FAH）缺乏引起的，该酶负责富马酰乙酸（FAA）的水解。因此，代谢物如马来酰乙酸酯、琥珀酰丙酮和FAA会积累。后者显示出诱变、细胞抑制和凋亡活性，并引起染色体不稳定。在此，我们证明FAA也引起细胞损伤，导致内质网（ER）应激信号。用致凋亡剂量的FAA （100 μ M）处理V79中国仓鼠肺细胞，可早期诱导内质网常驻伴侣GRP78/BiP，同时使eIF2 α磷酸化。FAA处理还导致随后诱导凋亡前蛋白CHOP （CEBP同源蛋白）转录因子以及晚期caspase-12的激活。从停用治疗性2-（2-硝基-4-三氟甲基苯甲酰）1,3环己二酮药物的fah(-)/ -小鼠获得的数据相似。然而，在该小鼠模型中，蛋白酶体活性也有所增加，表明er相关降解。这两种模型之间的差异可能是由于小鼠模型测量了遗传性酪氨酸血症I型中积累的所有代谢物的影响，而细胞模型仅测量外源性FAA的影响。
Hereditary tyrosinemia type I ( HTI) is the most severe disease of the tyrosine degradation pathway. HTI is caused by a deficiency of fumarylacetoacetate hydrolase ( FAH), the enzyme responsible for the hydrolysis of fumarylacetoacetate ( FAA). As a result, there is an accumulation of metabolites such as maleylacetoacetate, succinylacetone, and FAA. The latter was shown to display mutagenic, cytostatic, and apoptogenic activities and to cause chromosomal instability. Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum ( ER) stress signaling. Treatment of V79 Chinese hamster lung cells with an apoptogenic dose of FAA ( 100 mu M) causes an early induction of the ER resident chaperone GRP78/BiP and a simultaneous phosphorylation of the eIF2 alpha. FAA treatment also causes a subsequent induction of the proapoptotic CHOP ( CEBP homologous protein) transcription factor as well as a late activation of caspase-12. Data obtained from fah(-)/ - mice taken off the therapeutic 2-(2-nitro-4-trifluoromethylbenzoyl)1,3 cyclohexanedione drug are similar. However, in this mouse model, there is also an increase in proteasome activity indicative of ER-associated degradation. This difference observed between the two models may be due to the fact that the murine model measures the effects of all metabolites accumulating in hereditary tyrosinemia type I as opposed to the cellular model that only measures the effects of exogenous FAA.