GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis

Prathyush Pothukuchi; Ilenia Agliarulo; Marinella Pirozzi; Riccardo Rizzo; Domenico Russo; Gabriele Turacchio; Julian Nüchel; Jia Shu Yang; Charlotte Gehin; Laura Capolupo; Maria Jose Hernandez-Corbacho; Ansuman Biswas; Giovanna Vanacore; Nina Dathan; Takahiro Nitta; Petra Henklein; Mukund Thattai; Jin Ichi Inokuchi; Victor W. Hsu; Markus Plomann; Lina M. Obeid; Yusuf A. Hannun; Alberto Luini; Giovanni D’Angelo; Seetharaman Parashuraman

doi:10.15252/embj.2021107766

GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis

Prathyush Pothukuchi, Ilenia Agliarulo, Marinella Pirozzi, Riccardo Rizzo, Domenico Russo, Gabriele Turacchio, Julian Nüchel, Jia Shu Yang, Charlotte Gehin, Laura Capolupo, Maria Jose Hernandez-Corbacho, Ansuman Biswas, Giovanna Vanacore, Nina Dathan, Takahiro Nitta, Petra Henklein, Mukund Thattai, Jin Ichi Inokuchi, Victor W. Hsu, Markus PlomannLina M. Obeid, Yusuf A. Hannun, Alberto Luini, Giovanni D’Angelo, Seetharaman Parashuraman

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

25 Scopus citations

Abstract

The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.

Original language	English (US)
Article number	e107766
Journal	EMBO Journal
Volume	40
Issue number	20
DOIs	https://doi.org/10.15252/embj.2021107766
State	Published - Oct 18 2021
Externally published	Yes

Keywords

glucosylceramide synthase
glycosphingolipids
glycosylation
Golgi apparatus
GRASP55

ASJC Scopus subject areas

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

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Pothukuchi, P., Agliarulo, I., Pirozzi, M., Rizzo, R., Russo, D., Turacchio, G., Nüchel, J., Yang, J. S., Gehin, C., Capolupo, L., Hernandez-Corbacho, M. J., Biswas, A., Vanacore, G., Dathan, N., Nitta, T., Henklein, P., Thattai, M., Inokuchi, J. I., Hsu, V. W., ... Parashuraman, S. (2021). GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis. EMBO Journal, 40(20), Article e107766. https://doi.org/10.15252/embj.2021107766

Pothukuchi, P, Agliarulo, I, Pirozzi, M, Rizzo, R, Russo, D, Turacchio, G, Nüchel, J, Yang, JS, Gehin, C, Capolupo, L, Hernandez-Corbacho, MJ, Biswas, A, Vanacore, G, Dathan, N, Nitta, T, Henklein, P, Thattai, M, Inokuchi, JI, Hsu, VW, Plomann, M, Obeid, LM, Hannun, YA, Luini, A, D’Angelo, G & Parashuraman, S 2021, 'GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis', EMBO Journal, vol. 40, no. 20, e107766. https://doi.org/10.15252/embj.2021107766

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abstract = "The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.",

keywords = "glucosylceramide synthase, glycosphingolipids, glycosylation, Golgi apparatus, GRASP55",

author = "Prathyush Pothukuchi and Ilenia Agliarulo and Marinella Pirozzi and Riccardo Rizzo and Domenico Russo and Gabriele Turacchio and Julian N{\"u}chel and Yang, {Jia Shu} and Charlotte Gehin and Laura Capolupo and Hernandez-Corbacho, {Maria Jose} and Ansuman Biswas and Giovanna Vanacore and Nina Dathan and Takahiro Nitta and Petra Henklein and Mukund Thattai and Inokuchi, {Jin Ichi} and Hsu, {Victor W.} and Markus Plomann and Obeid, {Lina M.} and Hannun, {Yusuf A.} and Alberto Luini and Giovanni D{\textquoteright}Angelo and Seetharaman Parashuraman",

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year = "2021",

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doi = "10.15252/embj.2021107766",

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AU - Pothukuchi, Prathyush

AU - Agliarulo, Ilenia

AU - Pirozzi, Marinella

AU - Rizzo, Riccardo

AU - Russo, Domenico

AU - Turacchio, Gabriele

AU - Nüchel, Julian

AU - Yang, Jia Shu

AU - Gehin, Charlotte

AU - Capolupo, Laura

AU - Hernandez-Corbacho, Maria Jose

AU - Biswas, Ansuman

AU - Vanacore, Giovanna

AU - Dathan, Nina

AU - Nitta, Takahiro

AU - Henklein, Petra

AU - Thattai, Mukund

AU - Inokuchi, Jin Ichi

AU - Hsu, Victor W.

AU - Plomann, Markus

AU - Obeid, Lina M.

AU - Hannun, Yusuf A.

AU - Luini, Alberto

AU - D’Angelo, Giovanni

AU - Parashuraman, Seetharaman

PY - 2021/10/18

Y1 - 2021/10/18

N2 - The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.

AB - The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.

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KW - glycosphingolipids

KW - glycosylation

KW - Golgi apparatus

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GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis

Abstract

Keywords

ASJC Scopus subject areas

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