Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Avenida da República, 2780-157 Oeiras, Portugal.
Cell Rep. 2013 Nov 14;5(3):791-801. doi: 10.1016/j.celrep.2013.09.046. Epub 2013 Oct 31.
The unfolded protein response (UPR) is composed by homeostatic signaling pathways that are activated by excessive protein misfolding in the endoplasmic reticulum. Ire1 signaling is an important mediator of the UPR, leading to the activation of the transcription factor Xbp1. Here, we show that Drosophila Ire1 mutant photoreceptors have defects in the delivery of rhodopsin-1 to the rhabdomere and in the secretion of Spacemaker/Eyes Shut into the interrhabdomeral space. However, these defects are not observed in Xbp1 mutant photoreceptors. Ire1 mutant retinas have higher mRNA levels for targets of regulated Ire1-dependent decay (RIDD), including for the fatty acid transport protein (fatp). Importantly, the downregulation of fatp by RNAi rescues the rhodopsin-1 delivery defects observed in Ire1 mutant photoreceptors. Our results show that the role of Ire1 during photoreceptor differentiation is independent of Xbp1 function and demonstrate the physiological relevance of the RIDD mechanism in this specific paradigm.
未折叠蛋白反应(UPR)由内质网中蛋白质错误折叠过度激活的稳态信号通路组成。IRE1 信号是 UPR 的重要介质,导致转录因子 Xbp1 的激活。在这里,我们表明果蝇 Ire1 突变体感光器在向光小杆运输视紫红质-1和将 Spacemaker/Eyes Shut 分泌到间光小杆空间方面存在缺陷。然而,在 Xbp1 突变体感光器中没有观察到这些缺陷。Ire1 突变体视网膜中受调节的 Ire1 依赖性降解 (RIDD) 靶标(包括脂肪酸转运蛋白 (fatp))的 mRNA 水平更高。重要的是,fatp 的 RNAi 下调可挽救 Ire1 突变体感光器中观察到的视紫红质-1传递缺陷。我们的研究结果表明,IRE1 在感光器分化过程中的作用独立于 Xbp1 功能,并证明了 RIDD 机制在该特定范例中的生理相关性。