Trends in Molecular Medicine
ReviewCheckpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer
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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