The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization

Ella Doron-Mandel; Indrek Koppel; Ofri Abraham; Ida Rishal; Terika P. Smith; Courtney N. Buchanan; Pabitra K. Sahoo; Jan Kadlec; Juan A. Oses-Prieto; Riki Kawaguchi; Stefanie Alber; Eitan Erez Zahavi; Pierluigi Di Matteo; Agostina Di Pizio; Didi Andreas Song; Nataliya Okladnikov; Dalia Gordon; Shifra Ben-Dor; Rebecca Haffner-Krausz; Giovanni Coppola; Alma L. Burlingame; Pavel Jungwirth; Jeffery L. Twiss; Mike Fainzilber

doi:10.15252/embj.2020107158

The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization

Ella Doron-Mandel
, Indrek Koppel
, Ofri Abraham
, Ida Rishal
, Terika P. Smith
, Courtney N. Buchanan
, Pabitra K. Sahoo
, Jan Kadlec
, Juan A. Oses-Prieto
, Riki Kawaguchi
, Stefanie Alber
, Eitan Erez Zahavi
, Pierluigi Di Matteo
, Agostina Di Pizio
, Didi Andreas Song
, Nataliya Okladnikov
, Dalia Gordon
, Shifra Ben-Dor
, Rebecca Haffner-Krausz
, Giovanni Coppola

Alma L. Burlingame, Pavel Jungwirth, Jeffery L. Twiss, Mike Fainzilber

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

Abstract

Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.

Original language	American English
Article number	e107158
Journal	EMBO Journal
Volume	40
Issue number	20
DOIs	https://doi.org/10.15252/embj.2020107158
State	Published - Oct 18 2021
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

Keywords

axonal transport
cell size regulation
local translation
protein–membrane interaction
subcellular localization

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10.15252/embj.2020107158

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Doron-Mandel, E., Koppel, I., Abraham, O., Rishal, I., Smith, T. P., Buchanan, C. N., Sahoo, P. K., Kadlec, J., Oses-Prieto, J. A., Kawaguchi, R., Alber, S., Zahavi, E. E., Di Matteo, P., Di Pizio, A., Song, D. A., Okladnikov, N., Gordon, D., Ben-Dor, S., Haffner-Krausz, R., ... Fainzilber, M. (2021). The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization. EMBO Journal, 40(20), Article e107158. https://doi.org/10.15252/embj.2020107158

@article{50fa93b9edcb4f83947ada2fb31837a0,

title = "The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization",

abstract = "Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.",

keywords = "axonal transport, cell size regulation, local translation, protein–membrane interaction, subcellular localization",

author = "Ella Doron-Mandel and Indrek Koppel and Ofri Abraham and Ida Rishal and Smith, \{Terika P.\} and Buchanan, \{Courtney N.\} and Sahoo, \{Pabitra K.\} and Jan Kadlec and Oses-Prieto, \{Juan A.\} and Riki Kawaguchi and Stefanie Alber and Zahavi, \{Eitan Erez\} and \{Di Matteo\}, Pierluigi and \{Di Pizio\}, Agostina and Song, \{Didi Andreas\} and Nataliya Okladnikov and Dalia Gordon and Shifra Ben-Dor and Rebecca Haffner-Krausz and Giovanni Coppola and Burlingame, \{Alma L.\} and Pavel Jungwirth and Twiss, \{Jeffery L.\} and Mike Fainzilber",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license",

year = "2021",

month = oct,

day = "18",

doi = "10.15252/embj.2020107158",

language = "American English",

volume = "40",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "20",

}

Doron-Mandel, E, Koppel, I, Abraham, O, Rishal, I, Smith, TP, Buchanan, CN, Sahoo, PK, Kadlec, J, Oses-Prieto, JA, Kawaguchi, R, Alber, S, Zahavi, EE, Di Matteo, P, Di Pizio, A, Song, DA, Okladnikov, N, Gordon, D, Ben-Dor, S, Haffner-Krausz, R, Coppola, G, Burlingame, AL, Jungwirth, P, Twiss, JL & Fainzilber, M 2021, 'The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization', EMBO Journal, vol. 40, no. 20, e107158. https://doi.org/10.15252/embj.2020107158

TY - JOUR

T1 - The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization

AU - Doron-Mandel, Ella

AU - Koppel, Indrek

AU - Abraham, Ofri

AU - Rishal, Ida

AU - Smith, Terika P.

AU - Buchanan, Courtney N.

AU - Sahoo, Pabitra K.

AU - Kadlec, Jan

AU - Oses-Prieto, Juan A.

AU - Kawaguchi, Riki

AU - Alber, Stefanie

AU - Zahavi, Eitan Erez

AU - Di Matteo, Pierluigi

AU - Di Pizio, Agostina

AU - Song, Didi Andreas

AU - Okladnikov, Nataliya

AU - Gordon, Dalia

AU - Ben-Dor, Shifra

AU - Haffner-Krausz, Rebecca

AU - Coppola, Giovanni

AU - Burlingame, Alma L.

AU - Jungwirth, Pavel

AU - Twiss, Jeffery L.

AU - Fainzilber, Mike

PY - 2021/10/18

Y1 - 2021/10/18

N2 - Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.

AB - Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.

KW - axonal transport

KW - cell size regulation

KW - local translation

KW - protein–membrane interaction

KW - subcellular localization

UR - https://www.scopus.com/pages/publications/85114717476

UR - https://www.scopus.com/pages/publications/85114717476#tab=citedBy

U2 - 10.15252/embj.2020107158

DO - 10.15252/embj.2020107158

M3 - Article

C2 - 34515347

SN - 0261-4189

VL - 40

JO - EMBO Journal

JF - EMBO Journal

IS - 20

M1 - e107158

ER -

The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization

Abstract

ASJC Scopus subject areas

Keywords

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