TY - JOUR
T1 - Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development
AU - Yamada, Seiya
AU - Sato, Ayaka
AU - Ishihara, Naotada
AU - Akiyama, Hiroki
AU - Sakakibara, Shin ichi
N1 - Funding Information:
This work was funded by the Japan Society for the Promotion of Science grants-in-aid [KAKENHI] grant numbers 18K06491 (to H.A.) and 26430042 (to S.S.) and by Waseda University Grants for Special Research Projects 2018K-352 (to H.A.), 2015K-249 , and 2017K-301 (to S.S.).
Funding Information:
The authors would like to thank Dr. C. Guo (The University of Sheffield, UK) for sharing the YFP-Drp1-WT and YFP-Drp1-4KR plasmid, Dr. M. Kengaku for the myc-Drp1, and Dr. T. Nishida (Mie University, Japan) for the EGFP-Senp3 and EGFP-Senp5L. We would like to thank Editage (www.editage.com) for English language editing. We would also thank Mrs. Y. Ishiguro and D. Yasui (Waseda University) for technical assistance. This work was funded by the Japan Society for the Promotion of Science grants-in-aid [KAKENHI] grant numbers 18K06491 (to H.A.) and 26430042 (to S.S.) and by Waseda University Grants for Special Research Projects 2018K-352 (to H.A.), 2015K-249, and 2017K-301 (to S.S.). All authors have full access to the data of this study and take responsibility for its integrity and accuracy. Study concept and design: S.Y. H.A. and S.S. Acquisition of data: S.Y. A.S. H.A. and S.S. Preparation of experimental materials: S.Y. A.S. H.A. N.I. and S.S. Analysis and interpretation of data: S.Y. A.S. H.A. and S.S. Drafting of the manuscript: S.Y. H.A. and S.S. Critical revision of the manuscript: H.A. N.I. and S.S. Obtained funding: H.A. and S.S. The authors declare no conflicts of interest arising from the contents of this article.
Publisher Copyright:
© 2021 The Authors
PY - 2021/12/17
Y1 - 2021/12/17
N2 - Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology probably through controlling Drp1 ubiquitination and tubulation of the endoplasmic reticulum. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.
AB - Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology probably through controlling Drp1 ubiquitination and tubulation of the endoplasmic reticulum. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.
KW - Cellular neuroscience
KW - Molecular neuroscience
KW - Molecular physiology
UR - http://www.scopus.com/inward/record.url?scp=85121681729&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121681729&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103484
DO - 10.1016/j.isci.2021.103484
M3 - Article
AN - SCOPUS:85121681729
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 12
M1 - 103484
ER -