Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin

Sindhuja Gowrisankaran; Sébastien Houy; Johanna G.Peña del Castillo; Vicky Steubler; Monika Gelker; Jana Kroll; Paulo S. Pinheiro; Dirk Schwitters; Nils Halbsgut; Arndt Pechstein; Jan R.T. van Weering; Tanja Maritzen; Volker Haucke; Nuno Raimundo; Jakob B. Sørensen; Ira Milosevic

doi:10.1038/s41467-020-14993-8

Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin

Sindhuja Gowrisankaran, Sébastien Houy, Johanna G.Peña del Castillo, Vicky Steubler, Monika Gelker, Jana Kroll, Paulo S. Pinheiro, Dirk Schwitters, Nils Halbsgut, Arndt Pechstein, Jan R.T. van Weering, Tanja Maritzen, Volker Haucke, Nuno Raimundo, Jakob B. Sørensen, Ira Milosevic^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A’s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.

Original language	English
Article number	1266
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	11
Issue number	1
Early online date	9 Mar 2020
DOIs	https://doi.org/10.1038/s41467-020-14993-8
Publication status	Published - 1 Dec 2020

Funding

We thank the UMG animal facility, M. König and M. Costa for the excellent assistance and for help with genotyping, A. Witkowska for purified LDCVs, B. Tawfik for Syt1-pHluorin and Syt7-pHluorin constructs, and P. De Camilli (Yale University) for endo-philin KO mice and reagents. This work was supported by Schram-Stiftung T287/25457 and Deutsche Forschungsgemeinschaft (Emmy Noether Young Investigator Award MI-1702/1) to I.M., SySy fellowship to S.G., the Lundbeck foundation (P.S.P., S.H., J.B.S.), ERC Starting Grant 337327 (N.R.), ZonMW 91111009 (J.R.T.v.W.), Alzheimer’s Asso-ciaton AARG-17498856 (J.R.T.v.W.), the Novo Nordisk Foundation (J.B.S.) and the Independent Research Fund Denmark (S.H., J.B.S.).

Funders	Funder number
Schram-Stiftung T287/25457 and Deutsche Forschungsgemeinschaft	MI-1702/1
Alzheimer's Association	AARG-17498856
Seventh Framework Programme	952422, 337327
European Research Council
Deutsche Forschungsgemeinschaft
ZonMw	91111009
Lundbeckfonden
Novo Nordisk Fonden
Danmarks Frie Forskningsfond

UN SDGs

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

Access to Document

10.1038/s41467-020-14993-8

Persistent URL (handle)

Persistent link

Cite this

Gowrisankaran, S., Houy, S., del Castillo, J. G. P., Steubler, V., Gelker, M., Kroll, J., Pinheiro, P. S., Schwitters, D., Halbsgut, N., Pechstein, A., van Weering, J. R. T., Maritzen, T., Haucke, V., Raimundo, N., Sørensen, J. B., & Milosevic, I. (2020). Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin. Nature Communications, 11(1), 1-18. Article 1266. https://doi.org/10.1038/s41467-020-14993-8

@article{de51a4427d834304b73c9176ec2bb330,

title = "Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin",

abstract = "Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A{\textquoteright}s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.",

author = "Sindhuja Gowrisankaran and S{\'e}bastien Houy and {del Castillo}, {Johanna G.Pe{\~n}a} and Vicky Steubler and Monika Gelker and Jana Kroll and Pinheiro, {Paulo S.} and Dirk Schwitters and Nils Halbsgut and Arndt Pechstein and {van Weering}, {Jan R.T.} and Tanja Maritzen and Volker Haucke and Nuno Raimundo and S{\o}rensen, {Jakob B.} and Ira Milosevic",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14993-8",

language = "English",

volume = "11",

pages = "1--18",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Gowrisankaran, S, Houy, S, del Castillo, JGP, Steubler, V, Gelker, M, Kroll, J, Pinheiro, PS, Schwitters, D, Halbsgut, N, Pechstein, A, van Weering, JRT, Maritzen, T, Haucke, V, Raimundo, N, Sørensen, JB & Milosevic, I 2020, 'Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin', Nature Communications, vol. 11, no. 1, 1266, pp. 1-18. https://doi.org/10.1038/s41467-020-14993-8

TY - JOUR

T1 - Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin

AU - Gowrisankaran, Sindhuja

AU - Houy, Sébastien

AU - del Castillo, Johanna G.Peña

AU - Steubler, Vicky

AU - Gelker, Monika

AU - Kroll, Jana

AU - Pinheiro, Paulo S.

AU - Schwitters, Dirk

AU - Halbsgut, Nils

AU - Pechstein, Arndt

AU - van Weering, Jan R.T.

AU - Maritzen, Tanja

AU - Haucke, Volker

AU - Raimundo, Nuno

AU - Sørensen, Jakob B.

AU - Milosevic, Ira

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A’s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.

AB - Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A’s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.

UR - http://www.scopus.com/inward/record.url?scp=85081639106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85081639106&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14993-8

DO - 10.1038/s41467-020-14993-8

M3 - Article

C2 - 32152276

AN - SCOPUS:85081639106

SN - 2041-1723

VL - 11

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1266

ER -

Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin

Abstract

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this