TCTP and CSN4 control cell cycle progression and development by regulating CULLIN1 neddylation in plants and animals.

Léo Betsch,Judit Szécsi,Mohammed Bendahmane,Cécile Raynaud,Moussa Benhamed,Bertrand Mollereau,Florian Brioudes,Victor Girard,Pierre Chambrier,Nicolas Tissot,Julie Savarin,Garance Pontier,Barbara Wipperman,Véronique Boltz

doi:10.1371/journal.pgen.1007899

Abstract

Translationally Controlled Tumor Protein (TCTP) controls growth by regulating the G1/S transition during cell cycle progression. Our genetic interaction studies show that TCTP fulfills this role by interacting with CSN4, a subunit of the COP9 Signalosome complex, known to influence CULLIN-RING ubiquitin ligases activity by controlling CULLIN (CUL) neddylation status. In agreement with these data, downregulation of CSN4 in Arabidopsis and in tobacco cells leads to delayed G1/S transition comparable to that observed when TCTP is downregulated. Loss-of-function of AtTCTP leads to increased fraction of deneddylated CUL1, suggesting that AtTCTP interferes negatively with COP9 function. Similar defects in cell proliferation and CUL1 neddylation status were observed in Drosophila knockdown for dCSN4 or dTCTP, respectively, demonstrating a conserved mechanism between plants and animals. Together, our data show that CSN4 is the missing factor linking TCTP to the control of cell cycle progression and cell proliferation during organ development and open perspectives towards understanding TCTP’s role in organ development and disorders associated with TCTP miss-expression.

Highlights

The correct implementation of organs with unique shape, size and function is fundamental to the development of all multicellular organisms and is the result of coordinated cellular processes requiring key molecular actors
Translationally Controlled Tumor Protein (TCTP) controls mitotic growth by interacting with Constitutive Photomorphogenesis 9 (COP9) subunit CSN4 had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Immunoprecipitation followed by mass spectrometry (IP/MS) experiments were performed using protein extracts from Arabidopsis line expressing 35S::AtTCTP-GFP

Summary

Introduction

The correct implementation of organs with unique shape, size and function is fundamental to the development of all multicellular organisms and is the result of coordinated cellular processes requiring key molecular actors. One such key player in eukaryotes is the Translationally Controlled Tumor Protein (TCTP). How TCTP controls the G1/S transition and cell proliferation remains unknown in plants as in animals To better understand such a role, we searched for TCTP interacting proteins and identified that TCTP interacts physically with CSN4, one of the eight subunits of the Constitutive Photomorphogenesis 9 (COP9) Signalosome (CSN), initially discovered in plants [11,12] and conserved in eukaryotes [13]. The proper functioning of CRL has been shown to be absolutely required for various functions associated with the control of cell cycle, transcription, stress response, self-incompatibility, pathogen defense and hormones and light signaling [16,17,18]

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