| First Author | Gonuguntla S | Year | 2023 |
| Journal | J Biol Chem | Volume | 299 |
| Issue | 8 | Pages | 104803 |
| PubMed ID | 37172723 | Mgi Jnum | J:339459 |
| Mgi Id | MGI:7522569 | Doi | 10.1016/j.jbc.2023.104803 |
| Citation | Gonuguntla S, et al. (2023) Stress-induced pseudokinase TRB3 augments IL1beta signaling by interacting with Flightless homolog 1. J Biol Chem 299(8):104803 |
| abstractText | Interleukin-1beta is one of the most potent inducers of beta cell inflammation in the lead-up to type 1 diabetes. We have previously reported that IL1beta-stimulated pancreatic islets from mice with genetic ablation of stress-induced pseudokinase TRB3(TRB3KO) show attenuated activation kinetics for the MAP3K MLK3 and JNK stress kinases. However, JNK signaling constitutes only a portion of the cytokine-induced inflammatory response. Here we report that TRB3KO islets also show a decrease in amplitude and duration of IL1beta-induced phosphorylation of TAK1 and IKK, kinases that drive the potent NF-kappaB proinflammatory signaling pathway. We observed that TRB3KO islets display decreased cytokine-induced beta cell death, preceded by a decrease in select downstream NF-kappaB targets, including iNOS/NOS2 (inducible nitric oxide synthase), a mediator of beta cell dysfunction and death. Thus, loss of TRB3 attenuates both pathways required for a cytokine-inducible, proapoptotic response in beta cells. In order to better understand the molecular basis of TRB3-enhanced, post-receptor IL1beta signaling, we interrogated the TRB3 interactome using coimmunoprecipitation followed by mass spectrometry to identify immunomodulatory protein Flightless homolog 1 (Fli1) as a novel, TRB3-interacting protein. We show that TRB3 binds and disrupts Fli1-dependent sequestration of MyD88, thereby increasing availability of this most proximal adaptor required for IL1beta receptor-dependent signaling. Fli1 sequesters MyD88 in a multiprotein complex resulting in a brake on the assembly of downstream signaling complexes. By interacting with Fli1, we propose that TRB3 lifts the brake on IL1beta signaling to augment the proinflammatory response in beta cells. |
