Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.

中文翻译：

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未折叠的蛋白质反应通过 SNRPB 依赖性 RNA 剪接调节 ER 出口位点，并有助于骨骼发育。


剪接和内质网 （ER）-蛋白质稳态是最终调节细胞产生的功能蛋白的两个关键过程。然而，人们对这些过程相互作用的程度仍然知之甚少。在这里，我们将 SNRPB 和 Sm 环的其他成分确定为未折叠蛋白质反应的靶标和从 ER 输出的新型调节因子。从机制上讲，Sm-环调节 ER 输出机制成分的剪接，包括 Sec16A，ER 出口位点的一个组成部分。SNRPB 功能丧失与脑-肋-下颌综合征 （CCMS） 有因果关系，CCMS 是一种以骨缺损为特征的遗传病。我们表明，小鼠中 SNRPB 的杂合缺失导致让人想起 CCMS 的骨缺损，并且 SNRPB 的敲除会延迟 I 型胶原蛋白的运输。沉默 SNRPB 在体外抑制成骨，这可以通过过表达 Sec16A 来挽救。这种拯救表明 SNRPB 在成骨中的作用与其对 ER 输出的影响有关。最后，我们表明 SNRPB 是未折叠蛋白反应的靶标，这支持剪接体和 ER-蛋白稳态之间的机制联系。我们的工作突出了 Sm 环的组成部分作为蛋白质稳态网络中的一个新节点，阐明了 CCMS 病理生理学。