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T de Cristofaro, Istituto di Endocrinologia e Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Napoli, Italy
A Mascia, Istituto di Endocrinologia e Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Napoli, Italy
A Pappalardo, Istituto di Endocrinologia e Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Napoli, Italy
B D'Andrea, Istituto di Endocrinologia e Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Napoli, Italy
L Nitsch, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita' di Napoli Federico II, Napoli, Italy
M Zannini, Istituto di Endocrinologia e Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Napoli, 80131, Italy

Correspondence: Mariastella Zannini, Email: s.zannini{at}ieos.cnr.it

Abstract

The transcription factor Pax8 is involved in the morphogenesis of the thyroid gland and in the maintenance of the differentiated thyroid phenotype. Despite the critical role played by Pax8 during thyroid development and differentiation, very little is known on its post-translational modifications and on how these modifications may regulate its activity. We focused our attention on the study of a specific post-translational modification, i.e. sumoylation. Sumoylation is a dynamic and reversible process regulating gene expression by altering transcription factor stability, protein-protein interaction and subcellular localization of target proteins.

The analysis of Pax8 protein sequence revealed the presence of one sumoylation consensus motif (YKxE), strongly conserved among mammals, amphibians and fish. We demonstrated that Pax8 is sumoylated by the addition of a single SUMO (small ubiquitin-like modifier) molecule on its lysine residue 309 and that Pax8K309R, a substitution mutant in which the candidate lysine is replaced with an arginine, is no longer modified by SUMO. In addition, we analyzed whether PIASy, a member of the PIAS (Protein Inhibitor of Activated STAT) family of proteins, could function as a SUMO ligase and we demonstrated that indeed PIASy is able to increase the fraction of sumoylated Pax8.

Interestingly, we show that Pax8 is targeted in the SUMO nuclear bodies (SNBs), which are structures that regulate the nucleoplasmic concentration of transcription factors by SUMO trapping. Finally, we report here that the steady-state protein level of Pax8 is controlled by sumoylation.