Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF-α-induced human beta cell dysfunction and death – published online 29/03/2023

Arturo Roca-Rivada, Sandra Marín-Cañas, Maikel L. Colli, Chiara Vinci, Toshiaki Sawatani, Lorella Marselli, Miriam Cnop, Piero Marchetti, Decio L. Eizirik

TNF-α inhibition delays the progression of type 1 diabetes and circulating TNF-α is associated with aggressive forms of the disease. In this issue, Roca-Rivada et al (https://doi.org/10.1007/s00125-023-05908-5) describe the molecular mechanisms triggered by TNF-α that lead to human beta cell dysfunction and death when the type 1 diabetes candidate gene PTPN2 is silenced. Cells silenced for PTPN2 are more susceptible to the deleterious effect of TNF-α and IFN-α, showing increased beta cell apoptosis. The authors demonstrate that beta cell apoptosis is abolished by the parallel blocking of Bcl-2-like protein 2 (BIM) or c-Jun N-terminal kinase (JNK1), indicating an unexpected common pathway between TNF-α and IFN-α. They further identify JNK1 as a substrate for PTPN2 in beta cells. The authors conclude that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may benefit from therapies that inhibit TNF-α.

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