Inhibitory feedback control of NF-κB signalling in health and disease

Abstract

Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and ‘re-set’ inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical ‘inhibitor of κB kinases’ (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors.

IKKα plays a major role in canonical NF-κB signalling in colorectal cells

“…a stoichiometry or competition effect). Clearly, further work is required to assess the kinetics of TAK1 activation and feedback control [ 49 ] in the IKK KO cells.…”

“…This could reflect a technical limitation of the transient transfections or transiently transfected FLAG-tagged IKKα and endogenous IKKα may not be functionally equivalent. Alternatively, IKKα may facilitate recruitment of another kinase such as GSK3β and IKKε [ 48 , 49 ] to phosphorylate S468 in response to TNFα. First-in-class IKKα selective inhibitors have recently been described [ 50 ] and may be commercially available in the near future.…”

Kirenol: A Potential Natural Lead Molecule for a New Drug Design, Development, and Therapy for Inflammation

“…Despite the fact that TNF-α is one of the most powerful NF-κB activators, NF-κB regulates TNF-α expression as well. NF-κB can be activated by inflammatory cytokines, Gram-negative bacteria, a variety of disease-causing viruses, environmental toxins, chemical, physical, mechanical, and psychological stress, excessive glucose, fatty acids, UV radiation, cigarette smoke, and other disease-causing factors [ 46 , 47 , 48 , 49 , 50 ]. Hence, medicines that inhibit NF-κB and NF-κB-regulated gene products may be useful in the treatment of a wide range of inflammatory diseases.…”

Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms

“…The most promising molecules identified for their ability to inhibit this pathway target MyD88 downstream targets, namely IRAK1, IRAK4, and BTK. Among these, TL-895 (a potent irreversible BTK inhibitor) is currently used in phase 2 trials, both alone and in combination with MDM2 inhibitors [ 168 , 169 ] (NCT04655118, NCT04640532).…”