The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPs in Inflammation and Cancer

Abstract

Interleukin-1 (IL-1) is a large cytokine family closely related to innate immunity and inflammation. IL-1 proteins are key players in signaling pathways such as apoptosis, TLR, MAPK, NLR and NF-κB. The IL-1 pathway is also associated with cancer, and chronic inflammation increases the risk of tumor development via oncogenic mutations. Here we illustrate that the structures of interfaces between proteins in this pathway bearing the mutations may reveal how. Proteins are frequently regulated via their interactions, which can turn them ON or OFF. We show that oncogenic mutations are significantly at or adjoining interface regions, and can abolish (or enhance) the protein-protein interaction, making the protein constitutively active (or inactive, if it is a repressor). We combine known structures of protein-protein complexes and those that we have predicted for the IL-1 pathway, and integrate them with literature information. In the reconstructed pathway there are 104 interactions between proteins whose three dimensional structures are experimentally identified; only 15 have experimentally-determined structures of the interacting complexes. By predicting the protein-protein complexes throughout the pathway via the PRISM algorithm, the structural coverage increases from 15% to 71%. In silico mutagenesis and comparison of the predicted binding energies reveal the mechanisms of how oncogenic and single nucleotide polymorphism (SNP) mutations can abrogate the interactions or increase the binding affinity of the mutant to the native partner. Computational mapping of mutations on the interface of the predicted complexes may constitute a powerful strategy to explain the mechanisms of activation/inhibition. It can also help explain how an oncogenic mutation or SNP works.

Stabilization of ATF5 by TAK1–Nemo-Like Kinase Critically Regulates the Interleukin-1β-Stimulated C/EBP Signaling Pathway

“…It has been well documented that the propagation of IL-1␤ signaling mainly depends on MAPKs and their downstream effectors, which activate multiple transcription factors (22,23). Several reports have suggested that C/EBP is activated by IL-1␤ stimulation (16)(17)(18)(19)(20)(21); however, the underlying mechanism has not been fully described.…”

“…Because several studies showed that TAK1 is an upstream regulator of NLK (2,3,5,37,42,43) and a downstream effector of IL-1␤-triggered signaling (22,23,(44)(45)(46), we examined the roles of TAK1 in ATF5 stabilization and C/EBP activation. In accordance with the results of the NLK experiments, overexpression of TAK1 activated C/EBP in cooperation with ATF5 in HEK293T cells (Fig.…”

“…C/EBPs are involved in the interpretation of extracellular signals (15), including that initiated by the proinflammatory cytokine IL-1␤ (16)(17)(18)(19)(20)(21), via a variety of mechanisms. IL-1␤, the master cytokine in the IL-1 family, is associated with various cellular processes, including immunity, autophagy, and inflammation (22,23). IL-1␤ exerts its effects mainly by activating NF-B and MAPKs (22).…”

“…IL-1␤, the master cytokine in the IL-1 family, is associated with various cellular processes, including immunity, autophagy, and inflammation (22,23). IL-1␤ exerts its effects mainly by activating NF-B and MAPKs (22). Binding of IL-1␤ to its receptor, IL-1R, triggers a cascade that activates TAK1 to propagate downstream signaling (22,24).…”

“…IL-1␤ exerts its effects mainly by activating NF-B and MAPKs (22). Binding of IL-1␤ to its receptor, IL-1R, triggers a cascade that activates TAK1 to propagate downstream signaling (22,24). However, the molecular mechanism by which the IL-1␤ cascade regulates C/EBP remains obscure (16)(17)(18)(19)(20)(21).…”