Z-DNA and Z-RNA are left-handed double helix nucleic acid structures with poorly understood biological function 1 – 3 . Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM-1) is a nucleic acid sensor containing two Zα domains that bind Z-DNA 4 , 5 and Z-RNA 6 – 8 . ZBP1 mediates host-defence against certain viruses 6 , 7 , 9 – 14 by sensing viral nucleic acids 6 , 7 , 10 . RIPK1 deficiency or mutation of its RIP homotypic interaction motif (RHIM) triggers ZBP1-dependent necroptosis and inflammation in mice 15 , 16 , however, the mechanisms inducing ZBP1 activation in the absence of viral infection remain elusive. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM ( Ripk1 mR/mR ) and skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1 E-KO ), as well as colitis in mice with intestinal epithelial-specific FADD deficiency (FADD IEC-KO ). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that express RIPK1 with mutated RHIM or were treated with caspase inhibitors. Moreover, inhibition of nuclear export triggered Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, suggesting that ZBP1 may recognise Z-form nucleic acids (Z-NA) in the nucleus. We found that ZBP1 constitutively bound cellular double stranded RNA (dsRNA) in a Zα-dependent manner. Furthermore, endogenous retroelement (ERE)-derived complementary reads were detected in epidermal RNA, suggesting that ERE-derived dsRNA may act as Zα domain ligand triggering ZBP1 activation. Collectively, our results provide evidence that sensing of endogenous Z-NA by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions particularly in patients with mutations in the RIPK1 and CASPASE-8 genes 17 – 20 .

The aging process is accompanied by the onset of disease and a general decline in wellness. Insights into the aging process have revealed a number of cellular hallmarks of aging, among these epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Mitochondrial dysfunction increasingly appears to be a common factor connecting several of these hallmarks, driving the aging process and afflicting tissues throughout the body. Recent research has uncovered a much more complex involvement of mitochondria in the cell than has previously been appreciated and revealed novel ways in which mitochondrial defects feed into disease pathology. In this review we evaluate ways in which problems in mitochondria contribute to disease beyond the well-known mechanisms of oxidative stress and bioenergetic deficits, and we predict the direction that mitochondrial disease research will take in years to come.

Necroptosis complements apoptosis as a host defense pathway to stop virus infection. Herpes simplex virus shows a propensity to trigger necroptosis of mouse cells and mice even though cell death is blocked in human cells through UL39-encoded ICP6. This ribonucleotide reductase large subunit (R1) nucleates RHIM-dependent oligomerization of RIP3 kinase (RIPK3, also known as RIP3) in mouse cells but inhibits activation in cells from the natural human host. By interrogating the comparative behavior of ICP6-deficient viruses in mouse and human cells, here we unveil virus-induced necroptosis mediated by Z-DNA-binding protein 1 (ZBP1, also known as DAI). ZBP1 acts as a pathogen sensor to detect nascent RNA transcripts rather than input viral DNA or viral DNA generated through replication. Consistent with the implicated role of virus-induced necroptosis in restricting infection, viral pathogenesis is restored in Zbp1−/−, Ripk3−/− and Mlkl−/− mice. Thus, in addition to direct activation of RIPK3 via ICP6, HSV1 infection in mice and mouse cells triggers virus-induced necroptosis through ZBP1. Importantly, virus-induced necroptosis is also induced in human HT-29 cells by ICP6 mutant viruses; however, ZBP1 levels must be elevated for this pathway to be active. Thus, our studies reveal a common, species-independent role of this nucleic acid sensor to detect the presence of this virus. HSV1 ICP6 functions as a bona fide RHIM signaling inhibitor to block virus-induced necroptosis in its natural host. Altogether, ZBP1-dependent restriction of herpesvirus infection emerges as a potent antiviral armament of the innate immune system.

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan. Studies have shown various retrograde responses are activated in these animals, including the well-studied ATFS-1-dependent mitochondrial unfolded protein response (UPRmt). Such processes fall under the greater rubric of cellular surveillance mechanisms. Here we identify a novel p38 signaling cascade that is required to extend life when the mitochondrial electron transport chain is disrupted in worms, and which is blocked by disruption of the Mitochondrial-associated Degradation (MAD) pathway. This novel cascade is defined by DLK-1 (MAP3K), SEK-3 (MAP2K), PMK-3 (MAPK) and the reporter gene Ptbb-6::GFP. Inhibition of known mitochondrial retrograde responses does not alter induction of Ptbb-6::GFP, instead induction of this reporter often occurs in counterpoint to activation of SKN-1, which we show is under the control of ATFS-1. In those mitochondrial bioenergetic mutants which activate Ptbb-6::GFP, we find that dlk-1, sek-3 and pmk-3 are all required for their life extension.

Receptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-α, TLR ligands, and IFNs. Genetic ablation of Ripk1 results in perinatal lethality arising from both RIPK3-mediated necroptosis and FADD/caspase-8–driven apoptosis. IFNs are thought to contribute to the lethality of Ripk1-deficient mice by activating inopportune cell death during parturition, but how IFNs activate cell death in the absence of RIPK1 is not understood. In this study, we show that Z-form nucleic acid binding protein 1 (ZBP1; also known as DAI) drives IFN-stimulated cell death in settings of RIPK1 deficiency. IFN-activated Jak/STAT signaling induces robust expression of ZBP1, which complexes with RIPK3 in the absence of RIPK1 to trigger RIPK3-driven pathways of caspase-8–mediated apoptosis and MLKL-driven necroptosis. In vivo, deletion of either Zbp1 or core IFN signaling components prolong viability of Ripk1−/− mice for up to 3 mo beyond parturition. Together, these studies implicate ZBP1 as the dominant activator of IFN-driven RIPK3 activation and perinatal lethality in the absence of RIPK1.

SummaryDisruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long‐lived respiratory mutants generate elevated amounts of α‐ketoacids. These compounds are structurally related to α‐ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild‐type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia‐inducible factor‐1 (HIF‐1). We also find that an α‐ketoglutarate mimetic, 2,4‐pyridinedicarboxylic acid (2,4‐PDA), is alone sufficient to increase the lifespan of wild‐type worms and this effect is blocked by removal of HIF‐1. HIF‐1 is constitutively active in isp‐1(qm150) Mit mutants, and accordingly, 2,4‐PDA does not further increase their lifespan. Incubation of mouse 3T3‐L1 fibroblasts with life‐prolonging α‐ketoacids also results in HIF‐1α stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.

Herpesviruses are ubiquitous human pathogens that cause a wide range of health complications. Currently, there is an incomplete understanding of cellular factors that contribute to herpesvirus infection. Here, we report an antiviral necroptosis-based genetic screen to identify novel host cell factors required for infection with the β-herpesvirus murine cytomegalovirus (MCMV). Our genome-wide CRISPR-based screen harnessed the capacity of herpesvirus mutants that trigger antiviral necroptotic cell death upon early viral gene expression. Vascular endothelial growth factor (VEGF) and semaphorin-binding receptor Neuropilin-1 (Nrp-1) emerge as crucial determinants of MCMV infection. We find that elimination of Nrp-1 impairs early viral gene expression and reduces infection rates in endothelial cells, fibroblasts, and macrophages. Furthermore, preincubation of virus with soluble Nrp-1 dramatically inhibits infection by reducing virus attachment. Thus, Nrp-1 is a key determinant of the initial phase of MCMV infection.

A parthenolide-derivative with favourable pharmacokinetic properties and good activity against drug-resistant chronic lymphocytic leukaemia is reported.