Review
Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer

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Although long recognized as a component of inflamed tissues, the potential role of cell death as an active component contributing to tissue homeostasis, inflammation, and disease pathogenesis has only recently gained attention.

TNF is a pleiotropic cytokine with key roles in inflammation, triggering either NF-κB activation or RIPK1 kinase-dependent cell death.

Suppression of TNF-induced cell death is an active process controlled at multiple levels by diverse checkpoints, operating at both transcriptional and post-translational levels.

Signaling pathways of Ub-dependent phosphorylation of RIPK1 by IKK2 and MK2 have recently emerged as key checkpoints, limiting RIPK1 kinase activity and foiling TNF-mediated cytotoxicity. This, in turn, licenses the TNF-induced cytokine production that is necessary for a coordinated inflammatory response.

Accurate checkpoint control is vital, given that many pathogens target NF-κB and mitogen-activated protein kinase (MAPK) signaling to evade detection; however, this removes critical survival checkpoints that can unleash the cytotoxic potential of RIPK1, thus killing infected cells and safeguarding host survival.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that coordinates tissue homeostasis by regulating cytokine production, cell survival, and cell death. However, how life and death decisions are made in response to TNF is poorly understood. Many inflammatory pathologies are now recognized to be driven by aberrant TNF-induced cell death, which, in most circumstances, depends on the kinase Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Recent advances have identified ubiquitin (Ub)-mediated phosphorylation of RIPK1 as belonging to crucial checkpoints for cell fate in inflammation and infection. A better understanding of these checkpoints might lead to new approaches for the treatment of chronic inflammatory diseases fueled by aberrant RIPK1-induced cell death, and/or reveal novel strategies for anticancer immunotherapies, harnessing the ability of RIPK1 to trigger immunogenic cell death.

Section snippets

The Two Faces of TNF

Mammalian tissue repair following injury or infection critically depends on the coordination of cell death and inflammation. Dying cells can release a broad spectrum of highly conserved patterns (molecules) that are sensed by specialized pattern recognition receptors (PPRs; see Glossary), which subsequently trigger the induction of proinflammatory cytokines and chemokines [1]. Together, the release of cytokines, chemokines, and damage-associated molecular patterns (DAMPs) help direct repair

RIPK1 Is a Key Effector of TNF Signaling

The serine/threonine kinase RIPK1 harbors an N-terminal kinase domain, a 250-amino acid-long linker region or intermediate domain (ID), and a C-terminal RIP homotypic interaction motif (RHIM) and Death Domain (DD) (Figure 2). RIPK1 has important kinase-dependent and scaffolding functions that can trigger or inhibit cell death. While the Ser/Thr kinase activity of RIPK1 is essential for necroptosis [18], RIPK1-dependent apoptosis displays stimulus- and cell type-specific requirements of its

Checkpoints in TNF Signaling

In mice and humans, RIPK1 can be activated by a plethora of different death-inducing stimuli, including: TNF superfamily receptors (TNFR-1/2, Fas/CD95, TRAIL-R1/2, DR3, DR6, and Fn14), T cell receptors, interferons (IFNs), Toll-like receptors (TLR3 and TLR4) 37, 38, 39, 40, 41, 42, intracellular RNA and DNA sensors, an inhibited proteasome, as well as by stressors, such as calcium overload, endoplasmic reticulum (ER) stress, DNA damage, and ischemia-reperfusion injury 31, 43 (Figure 2). In the

Why so Many Checkpoints?

RIPK1-based secondary complexes are formed every time a cytokine receptor of the TNF superfamily, or Toll-like receptor family, is engaged, yet cells rarely respond with self-destruction [39]. The balance between life and death is delicately poised in favor of life. Hence, TNF, TRAIL, and LPS rarely trigger cell death under steady-state conditions, and various TNF signaling checkpoints ensure that life is the predominant outcome. However, these ligands and danger signals can potently destruct

Breaching the Barricades

Many microbial pathogens have evolved mechanisms to inhibit innate and acquired host immune responses to prevent their immune recognition and elimination [107]. Equally, in an arm’s race, eukaryotic cells can adopt strategies to circumvent pathogen adaptation mechanisms, preventing their replication and spreading (Figure 4). A striking example of this host–pathogen coevolution is exemplified by Y. enterocolitica. This bacterium causes RIPK1 kinase activity-dependent macrophage apoptosis through

Concluding Remarks

Inflammation is an essential defense response induced by infection or injury. Most, if not all, cellular stress responses, in addition to cell-autonomous adaptive changes, produce secreted factors that affect other cells tissues. This coordinates compensatory cell proliferation and tissue remodeling to replace malfunctioning or damaged tissues [114]. Inflammation is likely to have evolved as an adaptive response for restoring homeostasis [115]. While inflammatory cytokines can coordinate tissue

Acknowledgments

We would like to thank members of the Meier lab for helpful discussions and critical reading. We would like to apologize to the many authors whose work we could not cite due to space restrictions. A.A. is supported by an SNF fellowship and an MRC grant (MR/M019217/1). P.M. acknowledges support from Breast Cancer Now (CTR-QR14-007). We also acknowledge NHS funding to the NIHR Biomedical Research Centre.

Glossary

Apoptosis
process of programmed cell death executed by proteases of the caspase superfamily.
Caspases
a family of cysteine proteases involved in the initiation and execution of apoptosis. Caspases are not only involved in the regulation of cell death, but also have important roles in many other biological processes, such as cell migration, innate immune signaling, and cell differentiation.
Cellular inhibitor of apoptosis (cIAPs)
E3 Ub-ligases cIAP1 and cIAP2; these ligases have crucial roles in

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