Role of the spliceosomal subunit SNRPB in ER-proteostasis

The endoplasmic reticulum (ER) handles a third of all proteins that our cells produce. As such, the ER is a major regulator of protein homeostasis (proteostasis). The ER is equipped with a machinery that safeguards proteostasis, which is called the unfolded protein response (UPR). The UPR is a signaling network that relies on transcription, but it remains unknown how general splicing (the maturation of mRNA) is involved in proteostasis control. The current project will investigate the role of the spliceosomal component SNRPB in ER proteostasis. SNRPB is mutated in a rare genetic disease called Cerebro-Costo-Mandibular Syndrome that is characterized by bone malformations. The mechanistic link between SNRPB and bone disorder is currently unclear. We will use advanced microscopy techniques, genetic engineering and molecular cell biology to characterize the role of SNRPB in proteostasis control. Our project will be the first demonstration of the role for general splicing in proteostasis. Because proteostasis defects are often associated with bone malformation, we think that our work has the potential to provide the pathophysiological mechanism for the Cerebro-Costo-Mandibular Syndrome.