Caruso Marie-Elaine, Jenna Sarah, Bouchecareilh Marion, Baillie David L, Boismenu Daniel, Halawani Dalia, Latterich Martin, Chevet Eric
Team Avenir, INSERM U889, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Mol Cell Biol. 2008 Jul;28(13):4261-74. doi: 10.1128/MCB.02252-07. Epub 2008 May 5.
When endoplasmic reticulum (ER) homeostasis is perturbed, an adaptive mechanism is triggered and named the unfolded protein response (UPR). Thus far, three known UPR signaling branches (IRE-1, PERK, and ATF-6) mediate the reestablishment of ER functions but can also lead to apoptosis if ER stress is not alleviated. However, the understanding of the molecular mechanisms integrating the UPR to other ER functions, such as membrane traffic or endomembrane signaling, remains incomplete. We consequently sought to identify new regulators of UPR-dependent transcriptional mechanisms and focused on a family of proteins known to mediate, among other, ER-related functions: the small GTP-binding proteins of the RAS superfamily. To this end, we used transgenic UPR reporter Caenorhabditis elegans strains as a model to specifically silence small-GTPase expression. We show that the Rho subfamily member CRP-1 is an essential component of UPR-induced transcriptional events through its physical and genetic interactions with the AAA+ ATPase CDC-48. In addition, we describe a novel signaling module involving CRP-1 and CDC-48 which may directly link the UPR to DNA remodeling and transcription control.
当内质网（ER）稳态受到干扰时，一种适应性机制会被触发，称为未折叠蛋白反应（UPR）。到目前为止，三种已知的UPR信号分支（IRE-1、PERK和ATF-6）介导内质网功能的重建，但如果内质网应激得不到缓解，也会导致细胞凋亡。然而，对于将UPR与其他内质网功能（如膜运输或内膜信号传导）整合的分子机制的理解仍然不完整。因此，我们试图鉴定UPR依赖性转录机制的新调节因子，并聚焦于一类已知介导内质网相关功能的蛋白质家族：RAS超家族的小GTP结合蛋白。为此，我们使用转基因UPR报告秀丽隐杆线虫菌株作为模型，特异性沉默小GTP酶的表达。我们发现Rho亚家族成员CRP-1通过与AAA+ATP酶CDC-48的物理和遗传相互作用，是UPR诱导转录事件的重要组成部分。此外，我们描述了一个涉及CRP-1和CDC-48的新型信号模块，它可能直接将UPR与DNA重塑和转录控制联系起来。
