bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒11‒01
fourteen papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research

  1. Viruses. 2020 Oct 28. pii: E1221. [Epub ahead of print]12(11):
    Mandal P, McCormick AL, Mocarski ES.
      Cytomegaloviruses all encode the viral inhibitor of caspase-8-induced apoptosis (vICA). After binding to this initiator caspase, vICA blocks caspase-8 proteolytic activity and ability to activate caspase-3 and/or caspase-7. In this manner, vICA has long been known to prevent apoptosis triggered via tumor necrosis factor (TNF) family death receptor-dependent extrinsic signaling. Here, we employ fully wild-type murine cytomegalovirus (MCMV) and vICA-deficient MCMV (∆M36) to investigate the contribution of TNF signaling to apoptosis during infection of different cell types. ∆M36 shows the expected ability to kill mouse splenic hematopoietic cells, bone marrow-derived macrophages (BMDM), and dendritic cells (BMDC). Antibody blockade or genetic elimination of TNF protects myeloid cells from death, and caspase-8 activation accompanies cell death. Interferons, necroptosis, and pyroptotic gasdermin D (GSDMD) do not contribute to myeloid cell death. Human and murine fibroblasts or murine endothelial cells (SVEC4-10) normally insensitive to TNF become sensitized to ∆M36-induced apoptosis when treated with TNF or TNF-containing BMDM-conditioned medium. We demonstrate that myeloid cells are the natural source of TNF that triggers apoptosis in either myeloid (autocrine) or non-myeloid cells (paracrine) during ∆M36 infection of mice. Caspase-8 suppression by vICA emerges as key to subverting innate immune elimination of a wide variety of infected cell types.
    Keywords:  Caspase-8; DNA virus; HCMV; IFN; M36; MCMV; TNF; UL36; apoptosis; cell death; cytomegalovirus; extrinsic apoptosis; inflammation; intrinsic apoptosis; myeloid cells; necroptosis; pyroptosis; replication; vICA
  2. EMBO J. 2020 Oct 30. e105753
    Flores-Romero H, Ros U, Garcia-Saez AJ.
      The discovery of alternative signaling pathways that regulate cell death has revealed multiple strategies for promoting cell death with diverse consequences at the tissue and organism level. Despite the divergence in the molecular components involved, membrane permeabilization is a common theme in the execution of regulated cell death. In apoptosis, the permeabilization of the outer mitochondrial membrane by BAX and BAK releases apoptotic factors that initiate the caspase cascade and is considered the point of no return in cell death commitment. Pyroptosis and necroptosis also require the perforation of the plasma membrane at the execution step, which involves Gasdermins in pyroptosis, and MLKL in the case of necroptosis. Although BAX/BAK, Gasdermins and MLKL share certain molecular features like oligomerization, they form pores in different cellular membranes via distinct mechanisms. Here, we compare and contrast how BAX/BAK, Gasdermins, and MLKL alter membrane permeability from a structural and biophysical perspective and discuss the general principles of membrane permeabilization in the execution of regulated cell death.
    Keywords:  apoptosis; cell death; membrane pores; necroptosis; pyroptosis
  3. Angew Chem Int Ed Engl. 2020 Oct 27.
    Ghidini A, Cléry A, Halloy F, Allain FHT, Hall J.
      Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases, however targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitylation machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Here, we introduce RNA-PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA-binding site of the RBP, whereupon a conjugated E3-recruiting peptide derived from the HIF-1α protein directs the RBP for proteasomal degradation. We performed a proof-of-concept with the degradation of two RBPs - a stem cell factor LIN28 and a splicing factor RBFOX1 - and demonstrated their use in cancer cell lines. The RNA-PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.
    Keywords:  Lin28; PROTAC; RNA-binding protein; degrader; oligonucleotide
  4. ChemMedChem. 2020 Oct 28.
    Tian C, Burgess K.
      PROteolysis TArgeting Chimeras (PROTACs) are emerging as critical tools in biomedicinal chemistry and drug design, but they have limitations. These limitations include a lack of guiding principles when selecting suitable E3 ligases to induce ubiquitinylation, and problems degrading cell-surface receptors. This Highlight outlines some recent advances that circumvent some of these limitations, and new alternative methods to induce selective protein degradation.
    Keywords:  LYTACs; PROTACs; data mining; mAb conjugate; native mass spectrometry
  5. G3 (Bethesda). 2020 Oct 30. pii: g3.401800.2020. [Epub ahead of print]
    Kodra A, de la Cova C, Gerhold AR, Johnston LA.
      The process of apoptosis in epithelia involves activation of caspases, delamination of cells, and degradation of cellular components. Corpses and cellular debris are then rapidly cleared from the tissue by phagocytic blood cells. In studies of the Drosophila TNF, Eiger (Egr) and cell death in wing imaginal discs, the epithelial primordia of fly wings, we noticed that dying cells appeared to transiently accumulate in egr3 mutant wing discs, raising the possibility that their phagocytic engulfment by hemocytes was impaired. Further investigation revealed that lymph glands and circulating hemocytes from egr3 mutant larvae were completely devoid of NimC1 staining, a marker of phagocytic hemocytes. Genome sequencing uncovered mutations in the NimC1 coding region that are predicted to truncate the NimC1 protein before its transmembrane domain, and provide an explanation for the lack of NimC staining. The work that we report here demonstrates the presence of these NimC1 mutations in the widely used egr3 mutant, its sister allele, egr1 , and its parental strain, Regg1GS9830 As the egr3 and egr1 alleles have been used in numerous studies of immunity and cell death, it may be advisable to re-evaluate their associated phenotypes.
    Keywords:  Eiger/TNF; NimC1 mutations; cell competition; cell death; phagocytosis
  6. J Med Chem. 2020 Oct 26.
    Hatley RJD, Procopiou PA, McLachlan SP, Westendorf LE, Meanwell NA, Ewing WR, Macdonald SJF.
      Writing scientific articles is immensely rewarding but challenging. This Perspective provides the medicinal chemist with background and advice on the art and process of writing manuscripts and complements the instructions to authors provided by journals. Included are many tips that we wish we had known when we first started writing. Bibliometric data from seven medicinal chemistry journals between 2000 and 2019 are collated including Bioorganic and Medicinal Chemistry Letters and the Journal of Medicinal Chemistry. Although the overall number of articles has doubled, the output from 23 large pharma companies in the past decade has dropped significantly. Commentary is given on the entire process of writing original scientific articles, opinion articles, and reviews. Examples from our own papers and experience are shared including what typically motivates the writer, challenges commonly encountered, and how we find time to write. Finally, the benefits derived from much wider publishing of industrial medicinal chemistry are described.
  7. J Exp Med. 2021 Feb 01. pii: e20200476. [Epub ahead of print]218(2):
    Wirasinha RC, Davies AR, Srivastava M, Sheridan JM, Sng XYX, Delmonte OM, Dobbs K, Loh KL, Miosge LA, Lee CE, Chand R, Chan A, Yap JY, Keller MD, Chen K, Rossjohn J, La Gruta NL, Vinuesa CG, Reid HH, Lionakis MS, Notarangelo LD, Gray DHD, Goodnow CC, Cook MC, Daley SR.
      NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.
  8. JCI Insight. 2020 Oct 27. pii: 139837. [Epub ahead of print]
    Uzunparmak B, Gao M, Lindemann A, Erikson K, Wang L, Lin E, Frank SJ, Gleber-Netto FO, Zhao M, Skinner HD, Newton JM, Sikora AG, Myers JN, Pickering CR.
      Caspase 8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, in combination with pan-caspase inhibitors zVAD FMK or Emricasan and radiation. In a syngeneic mouse model of oral cancer, Birinapant, particularly when combined with radiation delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine-protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels render many HNSCC cell lines resistant to necroptosis, patient tumors maintain RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.
    Keywords:  Apoptosis pathways; Cell Biology; Head and neck cancer; Oncology; Radiation therapy
  9. Front Immunol. 2020 ;11 578038
    Pradel B, Robert-Hebmann V, Espert L.
      Autophagy is a lysosomal degradation pathway for intracellular components and is highly conserved across eukaryotes. This process is a key player in innate immunity and its activation has anti-microbial effects by directly targeting pathogens and also by regulating innate immune responses. Autophagy dysfunction is often associated with inflammatory diseases. Many studies have shown that it can also play a role in the control of innate immunity by preventing exacerbated inflammation and its harmful effects toward the host. The arms race between hosts and pathogens has led some viruses to evolve strategies that enable them to benefit from autophagy, either by directly hijacking the autophagy pathway for their life cycle, or by using its regulatory functions in innate immunity. The control of viral replication and spread involves the production of anti-viral cytokines. Controlling the signals that lead to production of these cytokines is a perfect way for viruses to escape from innate immune responses and establish successful infection. Published reports related to this last viral strategy have extensively grown in recent years. In this review we describe several links between autophagy and regulation of innate immune responses and we provide an overview of how viruses exploit these links for their own benefit.
    Keywords:  ATGs; autophagy; co-evolution; innate immunity; viruses
  10. Dokl Biochem Biophys. 2020 Sep;494(1): 252-255
    Morgun EI, Pozdniakova ED, Vorotelyak EA.
      Expression of cell death regulators RIPK-1 and RIPK-3 in mouse and human hair follicle structures was studied by immunohistochemistry. At anagen and catagen stages of mouse hair follicle, RIPK-1+ cells were located in the inner root sheath, whereas RIPK-3+ cells were found in the inner and outer root sheath, dermal papilla, and interfollicular epidermis. RIPK-1 expression intensity was low in the early anagen and increased as mature anagen and catagen approached. RIPK-1+ and RIPK-3+ cells were also found in human hair follicle. It is assumed that the role of necroptosis markers in hair follicle life activity is independent of programmed cell death and that they may have yet unknown functions and take part in noncanonical signal cascades.
    Keywords:  RIPK-1; RIPK-3; anagen; catagen; hair follicle; necroptosis; programmed cell death
  11. Nature. 2020 Oct 26.
    Brodsky IE.
    Keywords:  Cell biology; Immunology
  12. Dev Cell. 2020 Oct 26. pii: S1534-5807(20)30758-9. [Epub ahead of print]55(2): 109-111
    Tjin G, Purton LE.
      The generation of adult hematopoietic stem and progenitor cells (HSPCs) from embryonic and induced pluripotent stem cells (iPSCs) will provide therapeutic benefits but is currently elusive. In this issue of Developmental Cell, Frame et al. reveal that the inflammasome has a key role in HSPCs specification during endothelial-to-hematopoietic transition (EHT).
  13. J Burn Care Res. 2020 Oct 31. pii: iraa194. [Epub ahead of print]
    Faris J, Wilson J, Dolman HS, Isaacson A, Baylor AE, Tyburski JG, White MT.
      Toxic Epidermal Necrolysis (TEN) is a severe cutaneous reaction that can be life-threatening. In the United States, there are no established guidelines for the treatment of TEN. Supportive care including fluids and supportive therapies are the current recommendations. Research surrounding TEN involves mostly case studies or small, uncontrolled studies. Recent literature describes the use of TNF-blockers in the treatment of TEN with positive results. These case reports describe decreased time to re-epithelization, hospital length of stay, and minimal side effects. Conversely, we present three fatalities post administration of etanercept.
    Keywords:  Burns; Dermatology; Etanercept; Toxic Epidermal Necrolysis
  14. Cell. 2020 Oct 29. pii: S0092-8674(20)31318-0. [Epub ahead of print]183(3): 587-588
    Tarvin RD.
      Biology is entering a new era in which techniques honed in model systems can be applied to the expanding array of organisms with sequenced genomes. In this issue of Cell, van Giesen et al. (2020) characterize the molecular foundation of the touch-taste sensory system in octopus suckers.