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The microcephaly-associated protein YIPF5 differentially regulates ER export

Francesca Bruno1, Mihaela Anitei1, Domenico Di Fraia1

  • 1Leibniz Institute on Aging, Fritz-Lipmann Institute, Beutenbergstr. 11, 07745 Jena, Germany.

Iscience
|February 20, 2026
PubMed

Insights

YIPF5 protein regulates ER export, crucial for neuronal development. Its disruption causes microcephaly, epilepsy, and neonatal diabetes syndrome (MEDS2) by affecting protein transport and cell migration.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Genetics

Background:

  • YIPF5 is an endoplasmic reticulum (ER) membrane protein involved in ER-Golgi transport.
  • Mutations in YIPF5 lead to MEDS2, a severe early-childhood disorder.
  • YIPF5's precise role in protein export and its link to neurological defects are not fully understood.

Purpose of the Study:

  • To elucidate the function of YIPF5 in ER export and its contribution to neurological development.
  • To investigate the interaction between YIPF5 and the ER export receptor SURF4.
  • To understand the molecular mechanisms underlying YIPF5-associated developmental disorders.

Main Methods:

  • YIPF5 knockout and depletion cell models.
  • Analysis of cell surface protein profiles and secretome.
  • Wound-healing assays to assess cell migration.
  • Immunofluorescence microscopy to study protein localization (ERGIC53, Rab1).
  • Kinetic analysis of ER export.
  • In utero knockdown in mouse embryos.

Main Results:

  • YIPF5 directly interacts with SURF4 and regulates ER export of SURF4 cargoes.
  • YIPF5 deficiency alters cell surface proteins, reducing neuronal adhesion molecules and increasing ER chaperone secretion.
  • YIPF5 depletion enhances cell migration and disrupts SURF4 localization, forming abnormal ER tubules.
  • In utero Yipf5 knockdown causes premature neuronal migration and morphological defects in mouse brains.

Conclusions:

  • YIPF5 and SURF4 collaborate to coordinate the ER export of critical proteins.
  • Disruption of YIPF5 function underlies cortical development defects, potentially causing microcephaly.
  • YIPF5 plays a vital role in regulating neuronal migration and brain development.
Keywords:
Cell biologyNeuroscience

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