# The microcephaly-associated protein YIPF5 differentially regulates ER export

## TL;DR

This study shows that the YIPF5 protein helps regulate the transport of specific proteins from the endoplasmic reticulum, and its loss disrupts neuronal development, leading to microcephaly.

## Contribution

The study reveals YIPF5's role in ER export and its interaction with SURF4, linking these mechanisms to neurological disorders.

## Key findings

- YIPF5 knockout alters cell surface and secretome profiles, reducing neuronal adhesion molecules.
- YIPF5 depletion causes elongated ERGIC53- and Rab1-positive tubules and enhances cell migration.
- In utero Yipf5 knockdown leads to premature neuronal migration and abnormal morphology in mice.

## Abstract

YIPF5 is an ER-membrane protein implicated in ER-Golgi transport. Mutations in YIPF5 cause MEDS2 (microcephaly, epilepsy, and neonatal diabetes syndrome), a fatal disorder manifesting in early childhood. We demonstrate that YIPF5 is involved in ER export of a subset of proteins, including cargoes of the ER export receptor SURF4, with which it directly interacts. YIPF5 knockout cells display altered cell surface and secretome profiles, with reduced neuronal adhesion molecules and increased secretion of ER chaperones affecting migration. YIPF5 depletion enhances cell migration in a wound-healing assay and alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from ER exit sites. Kinetic analysis suggests that YIPF5 negatively regulates SURF4-mediated ER export. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology. Our findings suggest that YIPF5 and SURF4 coordinate ER export of key proteins and disruption may underlie cortical development defects leading to microcephaly.

•Loss of YIPF5 alters surfaceome and secretome, disrupting neuronal protein balance•YIPF5 interacts with the transport receptor SURF4•YIPF5-loss mislocalizes SURF4, producing elongated ERGIC53/Rab1-positive tubules•Yipf5 knockdown causes early neuronal migration and abnormal morphology

Loss of YIPF5 alters surfaceome and secretome, disrupting neuronal protein balance

YIPF5 interacts with the transport receptor SURF4

YIPF5-loss mislocalizes SURF4, producing elongated ERGIC53/Rab1-positive tubules

Yipf5 knockdown causes early neuronal migration and abnormal morphology

Neuroscience; Cell biology