Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development

Claudia Lentucci; Anna C. Belkina; Carly T. Cederquist; Michelle Chan; Holly E. Johnson; Sherry Prasad; Amanda Lopacinski; Barbara S. Nikolajczyk; Stefano Monti; Jennifer Snyder-Cappione; Bogdan Tanasa; M. Dafne Cardamone; Valentina Perissi

doi:10.1074/jbc.M116.755132

Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development

Claudia Lentucci
, Anna C. Belkina
, Carly T. Cederquist
, Michelle Chan
, Holly E. Johnson
, Sherry Prasad
, Amanda Lopacinski
, Barbara S. Nikolajczyk
, Stefano Monti
, Jennifer Snyder-Cappione
, Bogdan Tanasa
, M. Dafne Cardamone
, Valentina Perissi

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

22 Scopus citations

Abstract

Non-proteolytic ubiquitin signaling mediated by Lys⁶³ ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFoα signaling and lipid metabolism in the adipose tissue through modulation of Lys⁶³ ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.

Original language	English
Pages (from-to)	2754-2772
Number of pages	19
Journal	Journal of Biological Chemistry
Volume	292
Issue number	7
DOIs	https://doi.org/10.1074/jbc.M116.755132
State	Published - Feb 17 2017

Bibliographical note

Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Funding

This work was supported by awards from the Grunebaum Cancer Foundation and the Genomic Science Institute at Boston University and National Institutes of Health Grant R01DK100422 (to V. P.) and by a seed grant from the Medicine Department at Boston University School of Medicine (to V. P. and S. M.). This work was also supported by a National Research Service Award (NRSA) Individual Predoctoral Fellowship from the National Institutes of Health (F31DK108571) (to C.T.C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Funders	Funder number
Grunebaum Cancer Foundation
National Institutes of Health (NIH)	R01DK100422
National Institute of Diabetes and Digestive and Kidney Diseases	F31DK108571
Boston University School of Public Health/Boston University Medical Campus
Israel National Road Safety Authority
American Society for Biochemistry and Molecular Biology

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1074/jbc.M116.755132

Cite this

Lentucci, C., Belkina, A. C., Cederquist, C. T., Chan, M., Johnson, H. E., Prasad, S., Lopacinski, A., Nikolajczyk, B. S., Monti, S., Snyder-Cappione, J., Tanasa, B., Cardamone, M. D., & Perissi, V. (2017). Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development. Journal of Biological Chemistry, 292(7), 2754-2772. https://doi.org/10.1074/jbc.M116.755132

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title = "Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development",

abstract = "Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFoα signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.",

author = "Claudia Lentucci and Belkina, \{Anna C.\} and Cederquist, \{Carly T.\} and Michelle Chan and Johnson, \{Holly E.\} and Sherry Prasad and Amanda Lopacinski and Nikolajczyk, \{Barbara S.\} and Stefano Monti and Jennifer Snyder-Cappione and Bogdan Tanasa and Cardamone, \{M. Dafne\} and Valentina Perissi",

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year = "2017",

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doi = "10.1074/jbc.M116.755132",

language = "English",

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Lentucci, C, Belkina, AC, Cederquist, CT, Chan, M, Johnson, HE, Prasad, S, Lopacinski, A, Nikolajczyk, BS, Monti, S, Snyder-Cappione, J, Tanasa, B, Cardamone, MD & Perissi, V 2017, 'Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development', Journal of Biological Chemistry, vol. 292, no. 7, pp. 2754-2772. https://doi.org/10.1074/jbc.M116.755132

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AU - Lentucci, Claudia

AU - Belkina, Anna C.

AU - Cederquist, Carly T.

AU - Chan, Michelle

AU - Johnson, Holly E.

AU - Prasad, Sherry

AU - Lopacinski, Amanda

AU - Nikolajczyk, Barbara S.

AU - Monti, Stefano

AU - Snyder-Cappione, Jennifer

AU - Tanasa, Bogdan

AU - Cardamone, M. Dafne

AU - Perissi, Valentina

PY - 2017/2/17

Y1 - 2017/2/17

N2 - Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFoα signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.

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Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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