WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells

Linlin Wang, Hongyang Liu, Xiaofei Zhang, Eli Song, You Wang, Tao Xu () and Zonghong Li ()
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Linlin Wang: Guangzhou Laboratory
Hongyang Liu: Chinese Academy of Sciences
Xiaofei Zhang: University of Chinese Academy of Sciences
Eli Song: Chinese Academy of Sciences
You Wang: Chinese Academy of Sciences
Tao Xu: Guangzhou Laboratory
Zonghong Li: Guangzhou Laboratory

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The sorting of soluble secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex is mediated by coat protein complex II (COPII) vesicles and thought to required specific ER membrane cargo-receptor proteins. However, these receptors remain largely unknown. Herein, we show that ER to Golgi transfer of vesicular cargo proteins requires WFS1, an ER-associated membrane protein whose loss of function leads to Wolfram syndrome. Mechanistically, WFS1 directly binds to vesicular cargo proteins including proinsulin via its ER luminal C-terminal segment, whereas pathogenic mutations within this region disrupt the interaction. The specific ER export signal encoded in the cytosolic N-terminal segment of WFS1 is recognized by the COPII subunit SEC24, generating mature COPII vesicles that traffic to the Golgi complex. WFS1 deficiency leads to abnormal accumulation of proinsulin in the ER, impeding the proinsulin processing as well as insulin secretion. This work identifies a vesicular cargo receptor for ER export and suggests that impaired peptide hormone transport underlies diabetes resulting from pathogenic WFS1 mutations.

Date: 2021
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DOI: 10.1038/s41467-021-27344-y

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