The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.

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. Synopsis: RNA splicing and endoplasmic reticulum (ER) proteostasis are key to the overall control of mature protein production rates; however, the interaction between these processes is not well understood. In the following work, the spliceosome is shown to be a target of the unfolded protein response and a regulator of type-I collagen export. Silencing SNRPB and other spliceosome components alters ER export by regulating the splicing of Sec16A Loss of SNRPB results in type-I collagen trafficking defects in cell culture and osteogenesis defects in vivo SNRPB is regulated by the unfolded protein response (UPR) Our work contributes towards a better understanding of cerebro-costo-mandibular syndrome, a disease that is caused by loss of SNRPB Loss of SM-proteins alters the splicing of ER export factors which causes defects in ER-proteostasis and protein secretion. [ABSTRACT FROM AUTHOR]