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Cotranslational Proteolysis Dominates Glutathione Homeostasis to Support Proper Growth and Development^[C],[W]

^a Centre National de la Recherche Scientifique, Institut des Sciences du Végétal, Unité Propre de Recherche2355, Protein Maturation, Cell Fate, and Therapeutics, F-91198 Gif-sur-Yvette cedex, France
^b Université Paris-Sud, Institut Fédératif de Recherche87, Institut de Biotechnologie des Plantes, Plateforme Métabolisme-Métabolome, F-91405 Orsay, France
^c Centre National de la Recherche Scientifique, Institut Fédératif de Recherche87, Institut de Biotechnologie des Plantes, Plateforme Métabolisme-Métabolome, Unité Mixte de Recherche 8618, F-91405 Orsay, France
^d Université Paris-Sud, Plateforme de Protéomique, Institut Fédératif de Recherche87, Centre National de la Recherche Scientifique/Université Paris-Sud/Institut National de la Recherche Agronomique, F-91190 Gif-sur-Yvette, France
^e Centre National de la Recherche Scientifique, Plateforme de Protéomique, Institut Fédératif de Recherche87, F-91190 Gif-sur-Yvette, France
^f Institut National de la Recherche Agronomique, Plateforme de Protéomique, Institut Fédératif de Recherche87, F-91190 Gif-sur-Yvette, France

¹ Address correspondence to carmela.giglione{at}isv.cnrs-gif.fr.

The earliest proteolytic event affecting most proteins is the excision of the initiating Met (NME). This is an essential and ubiquitous cotranslational process tightly regulated in all eukaryotes. Currently, the effects of NME on unknown complex cellular networks and the ways in which its inhibition leads to developmental defects and cell growth arrest remain poorly understood. Here, we provide insight into the earliest molecular mechanisms associated with the inhibition of the NME process in Arabidopsis thaliana. We demonstrate that the developmental defects induced by NME inhibition are caused by an increase in cellular proteolytic activity, primarily induced by an increase in the number of proteins targeted for rapid degradation. This deregulation drives, through the increase of the free amino acids pool, a perturbation of the glutathione homeostasis, which corresponds to the earliest limiting, reversible step promoting the phenotype. We demonstrate that these effects are universally conserved and that the reestablishment of the appropriate glutathione status restores growth and proper development in various organisms. Finally, we describe a novel integrated model in which NME, protein N--acylation, proteolysis, and glutathione homeostasis operate in a sequentially regulated mechanism that directs both growth and development.