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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.

Understanding the intentions of others while observing their actions is a fundamental aspect of social behavior. However, the differences in neural and functional mechanisms between observing actions from the first-person perspective (1PP) and third-person perspective (3PP) are poorly understood. The present study had two aims: (1) to delineate the neural basis of action observation and understanding from the 1PP and 3PP; and (2) to identify whether there are different activation patterns during action observation and understanding from 1PP and 3PP. We used a blocked functional magnetic resonance imaging (fMRI) experimental design. Twenty-six right-handed participants observed interactions between the right hand and a cup from 1PP and 3PP. The results indicated that both 1PP and 3PP were associated with similar patterns of activation in key areas of the mirror neuron system underlying action observation and understanding. Importantly, besides of the core network of mirror neuron system, we also found that parts of the basal ganglia and limbic system were involved in action observation in both the 1PP and 3PP tasks, including the putamen, insula and hippocampus, providing a more complete understanding of the neural basis for action observation and understanding. Moreover, compared with the 3PP, the 1PP task caused more extensive and stronger activation. In contrast, the opposite comparison revealed that no regions exhibited significantly more activation in the 3PP compared with the 1PP condition. The current results have important implications for understanding the role of the core network underlying the mirror neuron system, as well as parts of the basal ganglia and limbic system, during action observation and understanding.