The microcephaly-associated protein YIPF5 differentially regulates ER export

Francesca Bruno; Mihaela Anitei; Domenico Di Fraia; William Durso; Therese Dau; Emilio Cirri; Mara Sannai; Christina Valkova; Julija Maldutyte; Elizabeth A. Miller; Ignacio Rubio; Vera Garloff; Noortje Kersten; Ginny G. Farias; Alessandro Ori; Iván Mestres; Federico Calegari; Christoph Kaether

doi:10.1016/j.isci.2026.114791

The microcephaly-associated protein YIPF5 differentially regulates ER export

Francesca Bruno
, Mihaela Anitei
, Domenico Di Fraia
, William Durso
, Therese Dau
, Emilio Cirri
, Mara Sannai
, Christina Valkova
, Julija Maldutyte
, Elizabeth A. Miller
, Ignacio Rubio
, Vera Garloff
, Noortje Kersten
, Ginny G. Farias
, Alessandro Ori
, Iván Mestres
, Federico Calegari
, Christoph Kaether (Lead / Corresponding author)

Molecular Cell and Developmental Biology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	114791
Pages (from-to)	1-18
Number of pages	18
Journal	iScience
Volume	29
Issue number	2
Early online date	27 Jan 2026
DOIs	https://doi.org/10.1016/j.isci.2026.114791
Publication status	Published - 20 Feb 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cell biology
Neuroscience

ASJC Scopus subject areas

General

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10.1016/j.isci.2026.114791Licence: CC BY

Final published versionFinal published version, 15.4 MBLicence: CC BY

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Bruno, F., Anitei, M., Di Fraia, D., Durso, W., Dau, T., Cirri, E., Sannai, M., Valkova, C., Maldutyte, J., Miller, E. A., Rubio, I., Garloff, V., Kersten, N., Farias, G. G., Ori, A., Mestres, I., Calegari, F., & Kaether, C. (2026). The microcephaly-associated protein YIPF5 differentially regulates ER export. iScience, 29(2), 1-18. Article 114791. https://doi.org/10.1016/j.isci.2026.114791

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title = "The microcephaly-associated protein YIPF5 differentially regulates ER export",

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.",

keywords = "Cell biology, Neuroscience",

author = "Francesca Bruno and Mihaela Anitei and \{Di Fraia\}, Domenico and William Durso and Therese Dau and Emilio Cirri and Mara Sannai and Christina Valkova and Julija Maldutyte and Miller, \{Elizabeth A.\} and Ignacio Rubio and Vera Garloff and Noortje Kersten and Farias, \{Ginny G.\} and Alessandro Ori and Iv{\'a}n Mestres and Federico Calegari and Christoph Kaether",

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doi = "10.1016/j.isci.2026.114791",

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Bruno, F, Anitei, M, Di Fraia, D, Durso, W, Dau, T, Cirri, E, Sannai, M, Valkova, C, Maldutyte, J, Miller, EA, Rubio, I, Garloff, V, Kersten, N, Farias, GG, Ori, A, Mestres, I, Calegari, F & Kaether, C 2026, 'The microcephaly-associated protein YIPF5 differentially regulates ER export', iScience, vol. 29, no. 2, 114791, pp. 1-18. https://doi.org/10.1016/j.isci.2026.114791

TY - JOUR

T1 - The microcephaly-associated protein YIPF5 differentially regulates ER export

AU - Bruno, Francesca

AU - Anitei, Mihaela

AU - Di Fraia, Domenico

AU - Durso, William

AU - Dau, Therese

AU - Cirri, Emilio

AU - Sannai, Mara

AU - Valkova, Christina

AU - Maldutyte, Julija

AU - Miller, Elizabeth A.

AU - Rubio, Ignacio

AU - Garloff, Vera

AU - Kersten, Noortje

AU - Farias, Ginny G.

AU - Ori, Alessandro

AU - Mestres, Iván

AU - Calegari, Federico

AU - Kaether, Christoph

PY - 2026/2/20

Y1 - 2026/2/20

N2 - 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.

AB - 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.

KW - Cell biology

KW - Neuroscience

UR - https://www.scopus.com/pages/publications/105029578986

U2 - 10.1016/j.isci.2026.114791

DO - 10.1016/j.isci.2026.114791

M3 - Article

AN - SCOPUS:105029578986

SN - 2589-0042

VL - 29

SP - 1

EP - 18

JO - iScience

JF - iScience

IS - 2

M1 - 114791

ER -

The microcephaly-associated protein YIPF5 differentially regulates ER export

Abstract

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Mechanisms Of Selective Protein Secretion: Towards Therapeutic Interventions

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The microcephaly-associated protein YIPF5 differentially regulates ER export

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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Mechanisms Of Selective Protein Secretion: Towards Therapeutic Interventions

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