Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract
Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract
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DOI：
10.1074/jbc.m109.060384
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发表时间：
2009-12-18
影响因子：
4.8
通讯作者：
Duncan, Melinda K.
中科院分区：
文献类型：
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作者：
Firtina, Zeynep;Danysh, Brian P.;Duncan, Melinda K.
由细胞外基质基因突变引起的人类疾病通常与白内障和晶状体囊破裂的风险增加有关。然而，在这些情况下白内障发病的潜在机制仍然是未知的。通过两种不同的小鼠模型，我们发现分泌途径中胶原链的积累激活了应激信号通路，称为未折叠蛋白反应（UPR）。在晶状体中表达异位Col4a3和Col4a4基因的转基因小鼠表现出IRE1、ATF6和PERK的激活，这与内质网的扩张和一般蛋白质翻译的衰减有关。在一组转基因晶状体纤维细胞中，转基因基因的表达对晶状体纤维细胞分化产生不利影响，最终导致细胞死亡。在Col4a1（+/Delta ex40）突变小鼠中，突变链的积累也导致了低水平的UPR激活。然而，突变体晶状体未诱导细胞死亡，这表明低水平的UPR激活不是促凋亡。总的来说，这些结果为UPR在白内障形成中的作用提供了体内证据，其作用是响应内质网中末端未折叠蛋白的积累。
Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1(+/Delta ex40) mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.