Details

Autor(en) / Beteiligte

• Molnár, Tamás
• Pallagi, Petra
• Tél, Bálint
• Király, Róbert
• Csoma, Eszter
• Jenei, Viktória
• Varga, Zsófia
• Gogolák, Péter
• Odile Hueber, Anne
• Máté, Zoltán
• Erdélyi, Ferenc
• Szabó, Gábor
• Pettkó‐Szandtner, Aladár
• Bácsi, Attila
• Virág, László
• Maléth, József
• Koncz, Gábor

Titel

Caspase‐9 acts as a regulator of necroptotic cell death

Ist Teil von

• The FEBS journal, 2021-11, Vol.288 (22), p.6476-6491

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Necroptosis is a regulated necrotic‐like cell death modality which has come into the focus of attention since it is known to contribute to the pathogenesis of many inflammatory and degenerative diseases as well as to tumor regulation. Based on current data, necroptosis serves as a backup mechanism when death receptor‐induced apoptosis is inhibited or absent. However, the necroptotic role of the proteins involved in mitochondrial apoptosis has not been investigated. Here, we demonstrated that the stimulation of several death and pattern recognition receptors induced necroptosis under caspase‐compromised conditions in wild‐type, but not in caspase‐9‐negative human Jurkat and murine MEF cells. Cerulein‐induced pancreatitis was significantly reduced in mice with acinar cell‐restricted caspase‐9 gene knockout. The absence of caspase‐9 led to impaired association of receptor‐interacting serine/threonine‐protein kinase 1 (RIPK1) and RIPK3 and resulted in decreased phosphorylation of RIP kinases, but the overexpression of RIPK1 or RIPK3 rescued the effect of caspase‐9 deficiency. Inhibition of either Aurora kinase A (AURKA) or its known substrate, glycogen synthase kinase 3β (GSK3ß) restored necroptosis sensitivity of caspase‐9‐deficient cells, indicating an interplay between caspase‐9 and AURKA‐mediated pathways to regulate necroptosis. Our findings suggest that caspase‐9 acts as a newly identified regulator of necroptosis, and thus, caspase‐9 provides a promising therapeutic target to manipulate the immunological outcome of cell death. Cell death is controlled by multiple interconnected pathways. It is known that death receptor‐mediated apoptosis dominates necroptosis to avoid unwanted inflammation. We report here that caspase‐9, which is well known as an initiator molecule for intrinsic apoptosis, is required for death and pattern recognition receptor‐induced necroptosis. Therefore, caspase‐9 can be responsible for regulating the transition between intrinsic apoptosis and necroptosis. ​