MK2–TNF–Signaling Comes Full Circle

MK2 regulates biosynthesis of TNF and other cytokines at the post-transcriptional level by phosphorylating and inactivating the mRNA-destabilizing and translation-inhibiting protein tristetraprolin (TTP). Phosphorylation of the TNF receptor-interacting protein kinase RIPK1 by MK2 inhibits autophosphorylation of RIPK1 and its integration into cytoplasmic cytotoxic complexes, and thus suppresses TNF-dependent apoptosis and necroptosis. The p38/MK2 pathway negatively regulates SMAC mimetic (SM)-induced RIPK1 kinase-dependent TNF production in myeloid cells. Thus, p38/MK2 coinhibition emerges as a therapeutic strategy to circumvent SM resistance in leukemia, aiding in autocrine TNF-induced apoptosis. Novel roles for MK2 are emerging in cancer, inflammation, and autophagy with the identification of novel substrates, such as TRIM29, BECN1, and CEP131, and their distinct loss-of-function phenotypes. MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis – pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond. MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis – pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond. sequence elements in the 3′-untranslated regions (3′-UTRs) of many tightly regulated transcripts including mRNAs of cytokines and cell-cycle regulators. They are rich in adenine and uridine bases, often harbor repeats of a core AUUUA sequence, and usually target mRNAs for rapid mRNA decay or suppress translation by interacting with an array of ARE-binding proteins. also known as caspase (CASP) 8 and FADD-like apoptosis regulator (CFLAR), cFLIP is an anti-apoptotic protein that binds to and inhibits CASP8 and CASP10. Multiple splice forms of cFLIP exist with altered functions, and their expression levels significantly affect the cytotoxic responses to death receptor ligation and chemotherapy. a family of related proteins which act as endogenous inhibitors of apoptotic death by suppressing caspase activation. They are characterized by the presence of one or more baculoviral IAP repeat (BIR) domains. The best-characterized members are cIAP1, cIAP2, and XIAP, which additionally possess a poly-ubiquitin-binding UBA (Ub-associated) domain and a RING (really interesting new gene) domain that identified them as ubiquitin E3 ligases. This ligase activity of cIAPs is involved in the regulation of NF-κB signaling. In addition, cIAP1/2-mediated ubiquitination of RIPK1 is crucial for preventing the assembly of RIPK1-containing cell death-promoting complexes. also known as endotoxin, LPS is an integral component of the cell wall of Gram-negative bacteria such as E. coli. It is one of the best-characterized pathogen-associated molecular pattern (PAMP) molecules which are recognized by the innate immune system as a means to detect bacterial infection. The cellular receptor for LPS consists of Toll-like receptor 4 (TLR4) and the coreceptor CD14 (cluster of differentiation 14). Binding of LPS to the receptor complex on myeloid cells initiates a strong proinflammatory response. a cytosolic death-promoting complex that is nucleated in response to genotoxic stress or IAP depletion. Its nucleation is dependent on RIPK1 activity, but is independent of death receptor stimulation. Cytosolic RIPK1 exist in a dormant state, being basally ubiquitinated by cIAP1/2. Genotoxic stress or depletion of IAPs by SMAC mimetics (SMs) leads to the deubiquitination, dimerization, and activation of RIPK1, which recruits FADD and CASP8 as core components to form the ripoptosome. cFLIP is part of a premature ripoptosome, and suppresses its cytotoxic potential by preventing CASP8 homodimerization and cleavage. The ripoptosome resembles complex IIb, which is seeded by death receptor signaling and can similarly induce RIPK1 activity-dependent apoptosis or RIPK3-dependent necrosis. also known as ZFP36, TTP is a zinc-finger non-enzymatic RNA-binding protein and a substrate for MK2. It is a feedback regulator of inflammatory signaling and mediator of post-transcriptional gene regulation. Non-phosphorylated TTP binds to AREs in the 3′-UTRs of mRNAs and subjects them to rapid degradation or translational suppression by recruiting further factors.