Whereas the apoptosis cell death pathway typically enables cells to undergo death in an immunologically silent manner, cell death by necroptosis induces cell lysis and release of cellular ...constituents known to elicit an immune response. Consequently, the origins of necroptosis likely originated in host defense against pathogens, although recently it has emerged that dysregulation of the pathway underlies many human pathologies. The past decade has seen a rapid advance in our understanding of the molecular mechanisms underlying necroptotic cell death, including the implication of the pseudokinase, mixed lineage kinase domain-like protein (MLKL), as the terminal effector in the pathway. Here, I review our current understanding of how MLKL is activated by the upstream receptor interacting protein kinase (RIPK)3, the proposed mechanism(s) by which MLKL kills cells, and recently described layers of regulation that tune MLKL's killing activity.
Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also ...directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1−/− mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1−/− progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1−/− neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1−/−Ripk3−/−, Ripk1−/−Mlkl−/−, and Ripk1−/−Myd88−/− mice prevented neonatal lethality, but only Ripk1−/−Ripk3−/−Casp8−/− mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.
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•RIPK1 delivers a TNF-dependent survival signal to HSC entering the bone marrow•RIPK1 can inhibit RIPK3/MLKL necroptosis•RIPK3/MLKL-dependent necroptosis causes IL-33 release in Ripk1−/− mice•Lethal, necroptosis-induced, systemic inflammation in Ripk1−/− mice is Myd88 dependent
Ripk1 deficiency induces RIPK3/MLKL-dependent necroptosis, triggers IL-33 release, and causes Myd88-dependent systemic inflammation and perinatal death. These phenotypes could be rescued by deletion of Ripk3 and Casp8, revealing a key function for RIPK1 in inhibiting necroptosis and limiting inflammation.
The problem of unsupervised learning and segmentation of hyperspectral images is a significant challenge in remote sensing. The high dimensionality of hyperspectral data, presence of substantial ...noise, and overlap of classes all contribute to the difficulty of automatically clustering and segmenting hyperspectral images. We propose an unsupervised learning technique called spectral-spatial diffusion learning (DLSS) that combines a geometric estimation of class modes with a diffusion-inspired labeling that incorporates both spectral and spatial information. The mode estimation incorporates the geometry of the hyperspectral data by using diffusion distance to promote learning a unique mode from each class. These class modes are then used to label all the points by a joint spectral-spatial nonlinear diffusion process. A related variation of DLSS is also discussed, which enables active learning by requesting labels for a very small number of well-chosen pixels, dramatically boosting overall clustering results. Extensive experimental analysis demonstrates the efficacy of the proposed methods against benchmark and state-of-the-art hyperspectral analysis techniques on a variety of real data sets, their robustness to choices of parameters, and their low computational complexity.
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in ...disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKL-induced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKL-dependent diseases.
Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted—ischemia—and then restored—reperfusion—leading to a burst of reactive oxygen species (ROS) from mitochondria. It has ...been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.
Ischemia-reperfusion (IR) injury occurs when circulation is disrupted and then restarted. Chouchani et al. propose a unifying framework for an array of data that could explain how ROS is specifically produced during IR, this providing testable hypotheses and new directions for therapies.
The Structural Basis of Necroptotic Cell Death Signaling Petrie, Emma J.; Czabotar, Peter E.; Murphy, James M.
Trends in biochemical sciences (Amsterdam. Regular ed.),
January 2019, 2019-01-00, 20190101, Letnik:
44, Številka:
1
Journal Article
Recenzirano
The recent implication of the cell death pathway, necroptosis, in innate immunity and a range of human pathologies has led to intense interest in the underlying molecular mechanism. Unlike the ...better-understood apoptosis pathway, necroptosis is a caspase-independent pathway that leads to cell lysis and release of immunogens downstream of death receptor and Toll-like receptor (TLR) ligation. Here we review the role of recent structural studies of the core machinery of the pathway, the protein kinases receptor-interacting protein kinase (RIPK)1 and RIPK3, and the terminal effector, the pseudokinase mixed lineage kinase domain-like protein (MLKL), in shaping our mechanistic understanding of necroptotic signaling. Structural studies have played a key role in establishing models that describe MLKL’s transition from a dormant monomer to a killer oligomer and revealing important interspecies differences.
Structures of component signaling modules in all known necroptosis effectors – RIPK1, RIPK3, and MLKL – have been reported over the past 5 years.
Recent NMR studies have provided insights into how RIPK1 and RIPK3 form high-molecular-weight fibrils via their RHIM motifs.
Recent structural and biophysical data highlight interspecies differences in the terminal effector MLKL. MLKL assembles into higher-order complexes: mouse MLKL forms trimers while the human protein is tetrameric. Structural differences in the executioner 4HB domain and the regulatory pseudokinase domain between mouse and human MLKL may reflect mechanistic differences.
Several models have been proposed to describe the mechanism by which MLKL permeabilizes the plasma membrane, leading to debate about the nature of the membrane aperture. Recent studies suggest a role for necroptotic coeffectors in regulating the susceptibility of membranes to MLKL-mediated permeabilization.
The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was ...first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haemopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the component FERM (4.1/ezrin/radixin/moesin)-SH2 (Src homology 2), pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain-containing proteins, SOCS (suppressors of cytokine signalling) proteins and LNK. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors.
Regulated necrosis in kidney ischemia-reperfusion injury Pefanis, Aspasia; Ierino, Francesco L.; Murphy, James M. ...
Kidney international,
August 2019, 2019-Aug, 2019-08-00, 20190801, Letnik:
96, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of ...perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions.
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