TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

Loïc Lionnard, Pauline Duc, Margs S. Brennan, Andrew J. Kueh, Martin Pal, Francesca Guardia, Barbara Mojsa, Maria Alessandra Damiano, Stéphan Mora, Iréna Lassot, Ramya Ravichandran, Claude Cochet, Abdel Aouacheria, Patrick Ryan Potts, Marco J. Herold, Solange Desagher, Jérôme Kucharczak

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Abstract

BCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin–proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here, we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death.

Original languageEnglish
JournalCell Death and Differentiation
Early online date24 Jul 2018
DOIs
Publication statusPublished - 24 Jul 2018

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Ubiquitination
Ubiquitin-Protein Ligases
Protein Stability
Half-Life
Melanoma
Neoplasms
Mitochondria
Cell Death
Phosphorylation
Enzymes
Proteins
Therapeutics
Tripartite Motif Proteins

Keywords

  • Oncogenes
  • Ubiquitylation

Cite this

Lionnard, Loïc ; Duc, Pauline ; Brennan, Margs S. ; Kueh, Andrew J. ; Pal, Martin ; Guardia, Francesca ; Mojsa, Barbara ; Damiano, Maria Alessandra ; Mora, Stéphan ; Lassot, Iréna ; Ravichandran, Ramya ; Cochet, Claude ; Aouacheria, Abdel ; Potts, Patrick Ryan ; Herold, Marco J. ; Desagher, Solange ; Kucharczak, Jérôme. / TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1. In: Cell Death and Differentiation. 2018.
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title = "TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1",
abstract = "BCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin–proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here, we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death.",
keywords = "Oncogenes, Ubiquitylation",
author = "Lo{\"i}c Lionnard and Pauline Duc and Brennan, {Margs S.} and Kueh, {Andrew J.} and Martin Pal and Francesca Guardia and Barbara Mojsa and Damiano, {Maria Alessandra} and St{\'e}phan Mora and Ir{\'e}na Lassot and Ramya Ravichandran and Claude Cochet and Abdel Aouacheria and Potts, {Patrick Ryan} and Herold, {Marco J.} and Solange Desagher and J{\'e}r{\^o}me Kucharczak",
note = "egional committees of Dr{\^o}me, H{\'e}rault and Loz{\`e}re (to J.K.) and Gard (to S.D.), the Centre National de la Recherche Scientifique (CNRS), Leukaemia Foundation Australia, and Cancer Council Victoria Venture Grant (to M.J.H.), World Cancer Research 15-0177 (to P.R.P.). L.L. was supported by the University of Montpellier, La Ligue Nationale contre le Cancer and by the Programme de mobilit{\'e} scientifique from the embassy of France in Australia. J.K. was supported by the University of Lyon and was recipient of a d{\'e}l{\'e}gation CNRS program.",
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Lionnard, L, Duc, P, Brennan, MS, Kueh, AJ, Pal, M, Guardia, F, Mojsa, B, Damiano, MA, Mora, S, Lassot, I, Ravichandran, R, Cochet, C, Aouacheria, A, Potts, PR, Herold, MJ, Desagher, S & Kucharczak, J 2018, 'TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1', Cell Death and Differentiation. https://doi.org/10.1038/s41418-018-0169-5

TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1. / Lionnard, Loïc; Duc, Pauline; Brennan, Margs S.; Kueh, Andrew J.; Pal, Martin; Guardia, Francesca; Mojsa, Barbara; Damiano, Maria Alessandra; Mora, Stéphan; Lassot, Iréna; Ravichandran, Ramya; Cochet, Claude; Aouacheria, Abdel; Potts, Patrick Ryan; Herold, Marco J.; Desagher, Solange; Kucharczak, Jérôme.

In: Cell Death and Differentiation, 24.07.2018.

Research output: Contribution to journalArticle

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T1 - TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

AU - Lionnard, Loïc

AU - Duc, Pauline

AU - Brennan, Margs S.

AU - Kueh, Andrew J.

AU - Pal, Martin

AU - Guardia, Francesca

AU - Mojsa, Barbara

AU - Damiano, Maria Alessandra

AU - Mora, Stéphan

AU - Lassot, Iréna

AU - Ravichandran, Ramya

AU - Cochet, Claude

AU - Aouacheria, Abdel

AU - Potts, Patrick Ryan

AU - Herold, Marco J.

AU - Desagher, Solange

AU - Kucharczak, Jérôme

N1 - egional committees of Drôme, Hérault and Lozère (to J.K.) and Gard (to S.D.), the Centre National de la Recherche Scientifique (CNRS), Leukaemia Foundation Australia, and Cancer Council Victoria Venture Grant (to M.J.H.), World Cancer Research 15-0177 (to P.R.P.). L.L. was supported by the University of Montpellier, La Ligue Nationale contre le Cancer and by the Programme de mobilité scientifique from the embassy of France in Australia. J.K. was supported by the University of Lyon and was recipient of a délégation CNRS program.

PY - 2018/7/24

Y1 - 2018/7/24

N2 - BCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin–proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here, we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death.

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KW - Oncogenes

KW - Ubiquitylation

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