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

Muhammad Zahoor; Yanchen Dong; Marco Preussner; Veronika Reiterer; Sabrina Shameen Alam; Margot Haun; Utku Horzum; Yannick Frey; Renata Hajdu; Stephan Geley; Valerie Cormier-Daire; Florian Heyd; Loydie A Jerome-Majewska; Hesso Farhan

doi:10.1038/s44318-024-00208-z

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

EMBO J. 2024 Oct;43(19):4228-4247. doi: 10.1038/s44318-024-00208-z. Epub 2024 Aug 19.

Authors

Muhammad Zahoor^#^{1

2}, Yanchen Dong^#^{3

4}, Marco Preussner⁵, Veronika Reiterer⁶, Sabrina Shameen Alam^{3

4}, Margot Haun⁶, Utku Horzum⁶, Yannick Frey⁶, Renata Hajdu⁶, Stephan Geley⁶, Valerie Cormier-Daire⁷, Florian Heyd⁵, Loydie A Jerome-Majewska^{8

9

10

11}, Hesso Farhan^{12

13}

Affiliations

¹ Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. [email protected].
² Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. [email protected].
³ Research Institute of the McGill University Health Centre at Glen Site, Montreal, QC, H4A 3J1, Canada.
⁴ Department of Human Genetics, McGill University, Montreal, QC, H3A 0G1, Canada.
⁵ Institute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of RNA Biochemistry, Takustrasse 6, 14195, Berlin, Germany.
⁶ Institute of Pathophysiology, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria.
⁷ Clinical Genetics Department, Université de Paris, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital, Paris, France.
⁸ Research Institute of the McGill University Health Centre at Glen Site, Montreal, QC, H4A 3J1, Canada. [email protected].
⁹ Department of Human Genetics, McGill University, Montreal, QC, H3A 0G1, Canada. [email protected].
¹⁰ Department of Anatomy and Cell Biology, McGill University, Montreal, QC, H3A 2B2, Canada. [email protected].
¹¹ Department of Pediatrics, McGill University, Montreal, QC, H4A 3J1, Canada. [email protected].
¹² Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. [email protected].
¹³ Institute of Pathophysiology, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria. [email protected].

^# Contributed equally.

Abstract

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.

Keywords: COPII; Endoplasmic Reticulum; Proteostasis; Sec16A; Splicing.

MeSH terms

Animals
Bone Development* / genetics
Endoplasmic Reticulum* / metabolism
Humans
Mice
Mice, Knockout
Osteogenesis / genetics
RNA Splicing*
Unfolded Protein Response*

Abstract

MeSH terms

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