TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

Cancer cells alter their metabolism in order to support their rapid proliferation and expansion across the body. In particular, tumor cells, rather than fueling glucose in the oxidative phosphorylation pathway, generally use glucose for aerobic glycolysis. In this review, we discuss some of the mechanisms thought to be responsible for the acquisition of a glycolytic phenotype in cancer cells and how the switch towards glycolysis represents a selective growth advantage. Glucose deprivation can activate oncogenes and these can upregulate proteins involved in aerobic glycolysis. In turn, proteins implicated in increased glycolysis can render tumor cells more resistant to apoptosis. Aerobic glycolysis induces acidification of the tumor environment, favoring the development of a more aggressive and invasive phenotype. Altering the pH around tumors might represent a way to hamper tumor development as suggested by a recent work demonstrating that bicarbonate, which increases the pH of tumors, prevented spontaneous metastatization. The acquisition of a glycolytic phenotype by transformed cells confers a selective growth advantage to these cells. Interfering with aerobic glycolysis, therefore, represents a potentially effective strategy to selectively target cancer cells.

Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10⁺, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-κB signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.

Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.

On binding to their cognate ligands, death receptors can initiate a cascade of events that can result in two distinct outcomes: gene expression and cell death. The study of three different death receptor–ligand systems, the tumor necrosis factor (TNF)–TNF receptor 1 (TNFR1), the CD95L–CD95, and the TNF-related apoptosis-inducing ligand (TRAIL)–TRAIL-R1/2 system, has drawn the attention of generations of scientists over the past 50 years. This scientific journey, as often happens in science, has been anything but a straight line to success and discoveries in this field were often made by serendipity, catching the scientists by surprise. However, as Louis Pasteur pointed out, luck prefers the prepared mind. It is therefore not surprising that the most impactful discovery of the field to date, the fact that TNF inhibition serves as an effective treatment for several inflammatory and autoimmune diseases, has been like this. Luckily, the scientists who made this discovery were prepared and, most importantly, determined to harness their discovery for therapeutic benefit. Today's research on these death receptor–ligand systems has led to the discovery of a causal link between cell death induced by a variety of these systems and inflammation. In this review, we explain why we predict that therapeutic exploitation of this discovery may profoundly impact the future treatment of inflammatory disease and cancer.