The role of general splicing in endoplasmic reticulum (ER)-proteostasis remains poorly understood. Here, we identify SNRPB, a component of the spliceosome, as a novel regulator of export from the ER. Mechanistically, SNRPB regulates the splicing of components of the ER export machinery, including Sec16A, a regulator 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 intracellular accumulation of type-1 collagen as well as bone defects reminiscent of CCMS. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This 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 (UPR), which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights SNRPB as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.

Identification of a link between splicing and endoplasmic reticulum proteostasis