Estudio de las señales tempranas que dirigen la regeneración de epitelios

[eng] The mechanisms through which cells communicate to initiate a regenerative response remains unsolved. It is established that Reactive Oxygen Species (ROS) are early signals released from injured cells that propagates to stimulate the replacement of lost tissue. ROS triggers the activation of the stress activated protein kinases (SAPKs) p38 and JNK via phosphorylation. Prolonged or elevated activation of these kinases may induce apoptosis, while brief or minimal activation can foster regeneration. Nonetheless, the precise connection between ROS generation and the initiation of regenerative signaling pathways remains incompletely elucidated. To this aim, we used Drosophila wing imaginal discs as a model system due to its well-characterized regenerative ability aCer injury or genetic ablation. We found that The Apoptosis signal-regulating kinase 1 (Ask1) emerges as a pivotal factor for driving regenerative growth. It exhibits the remarkable ability to sense ROS both in dying and living cells. However, in living cells, its activation is intricately regulated by nutrient sensitivity through Akt, a core kinase of the insulin (PI3K/Akt) pathway. Akt phosphorylates Ask1 at Ser83, an indispensable event for Ask1 to catalyze the activation of p38, albeit not JNK. Moreover, nutrient restriction or mutations targeting Ser83 of the Drosophila Ask1 block regeneration. Impediments that can be rescued by the ectopic activation of p38, but not JNK. Besides, ROS plays a critical role in the ligand-independent TNF receptor (TNFR) Wengen (Wgn) activation in response to apoptosis. Wgn, but not Grindelwald (Grnd), exhibits a protective mechanism mediated by the signaling molecule TRAF1, ultimately leading to the activation of the Ask1-p38 axis. This stress-response mechanism could be evolutionary conserved as Wgn cysteine rich domain (CRD) shows greater similarity with TNFR families found in other deuterostomes. Our findings underscore a non-autonomous activation of a ROS sensing mechanism orchestrated by Ask1, Akt1 and Wgn that results in the activation of a p38-dependent regenerative response.