Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment

Lucie Ruiz (1) , Tatyana Gurlo (2) , Magalie A Ravier (1) , Anne Wojtusciszyn (3, 1, 4) , Julia Mathieu (1) , Matthew R. Brown , Christophe Broca (3, 4) , Gyslaine Bertrand (1) , Peter C. Butler , Aleksey V. Matveyenko , Stéphane Dalle (1) , Safia Costes (1)

1 IGF - Institut de Génomique Fonctionnelle
2 David Geffen School of Medicine [Los Angeles]
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)

In type 2 diabetes, amyloid oligomers, chronic hyperglycemia, lipotoxicity, and pro-inflammatory cytokines are detrimental to beta-cells, causing apoptosis and impaired insulin secretion. The histone acetyl transferase p300, involved in remodeling of chromatin structure by epigenetic mechanisms, is a key ubiquitous activator of the transcriptional machinery. In this study, we report that loss of p300 acetyl transferase activity and expression leads to beta-cell apoptosis, and most importantly, that stress situations known to be associated with diabetes alter p300 levels and functional integrity. We found that proteasomal degradation is the mechanism subserving p300 loss in beta-cells exposed to hyperglycemia or pro-inflammatory cytokines. We also report that melatonin, a hormone produced in the pineal gland and known to play key roles in beta-cell health, preserves p300 levels altered by these toxic conditions. Collectively, these data imply an important role for p300 in the pathophysiology of diabetes.

Domaines: Biochimie, Biologie Moléculaire; Endocrinologie et métabolisme

Lucie Ruiz, Tatyana Gurlo, Magalie A Ravier, Anne Wojtusciszyn, Julia Mathieu, et al.. Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment. Cell Death Discovery, 2018, 9 (6), pp.600. ⟨10.1038/s41419-018-0603-0⟩. ⟨hal-02320439⟩