The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Abstract

Tumor necrosis factor alpha (TNF; TNFα) is a critical regulator of immune responses in healthy organisms and in disease. TNF is involved in the development and proper functioning of the immune system by mediating cell survival and cell death inducing signaling. TNF stimulated signaling pathways are tightly regulated by a series of phosphorylation and ubiquitination events, which enable timely association of TNF receptors-associated intracellular signaling complexes. Disruption of these signaling events can disturb the balance and the composition of signaling complexes, potentially resulting in severe inflammatory diseases.

Keywords: NEMO; RIP1 (RIPK1); RIP3 kinase; RIPK1 inhibitors; TNF; apoptosis; necroptois.

FIGURE 1

TNF induced canonical NF-κB pathway. TNF stimulation triggers the recruitment of TRADD, TRAF2, RIP1, and c-IAP1/2 to TNFR1. E3 ligases c-IAP1/2 polyubiquitinate themselves and RIP1 with K11 and K63 ubiquitin linkages, creating a platform for further recruitment of LUBAC. LUBAC mediates linear polyubiquitin, resulting in gene expression via the IKK complex. Several DUBs have been implicated in the regulation of TNFR1-associated complex I by removing linear (CYLD and OTULIN) or K63-linked polyubiquitin chains (A20 and CYLD).

FIGURE 2

TNF induced cell death signaling. Inhibition of NF-κB and MAPK signaling can divert TNF-mediated signaling to the formation of an intracellular complex II centered on FADD and caspase-8 in a RIP1-dependent apoptotic cell death. This cell death pathway can be augmented by A20 or by the absence of the E3 ligases c-IAP1/2 or LUBAC, thereby eliminating the ubiquitination of complex I components and promoting the switch to complex II. Activation of RIP1-dependent cell death under caspase-8 inhibited or deficient conditions can lead to a necroptotic form of cell death that is mediated by kinase activity of RIP1 and RIP3, and results in the activation of MLKL and membrane permeabilization.

FIGURE 3

Human mutations and genetic models in TNF signaling pathways. Mutations in multiple components of TNF signaling leading to functional dysregulation of E3 ligase complex LUBAC, deubiquitinases A20 and OTULIN, ubiquitin-binding protein NEMO, ligand TNF or pro-death kinase RIP1 can cause inflammatory diseases and/or immunodeficiency.