bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020–04–05
twenty-one papers selected by
John Silke, Walter and Eliza Hall Institute of Medical Research
  1. Identification of MLKL membrane translocation as a checkpoint in necroptotic cell death using Monobodies.
  2. Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection.
  3. On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function.
  4. Double agents of cell death: novel emerging functions of apoptotic regulators.
  5. Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis.
  6. Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.
  7. Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality.
  8. A20 and Cell Death-driven Inflammation.
  9. Robust high-throughput assays to assess discrete steps in ubiquitination and related cascades.
  10. OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer.
  11. TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice.
  12. RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells.
  13. The role of phosphatidylserine recognition receptors in multiple biological functions.
  14. Not So FASt: Tumor Cells Resisting Death Drive CAR T-cell Dysfunction.
  15. Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways.
  16. Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut.
  17. Editorial Overview: Tracking the ties that bind: Emerging technologies to profile biomolecular interactions in native environments.
  18. NOD1 and NOD2 activation by diverse stimuli: a possible role for sensing pathogen-induced ER stress.
  19. Understanding cachexia in the context of metastatic progression.
  20. "Make way": Pathogen exploitation of membrane traffic.
  21. The Multifactorial Role of PARP-1 in Tumor Microenvironment.
  1. Proc Natl Acad Sci U S A. 2020 Mar 31. pii: 201919960. [Epub ahead of print]
    Identification of MLKL membrane translocation as a checkpoint in necroptotic cell death using Monobodies.
    Emma J Petrie, Richard W Birkinshaw, Akiko Koide, Eric Denbaum, Joanne M Hildebrand, Sarah E Garnish, Katherine A Davies, Jarrod J Sandow, Andre L Samson, Xavier Gavin, Cheree Fitzgibbon, Samuel N Young, Patrick J Hennessy, Phoebe P C Smith, Andrew I Webb, Peter E Czabotar, Shohei Koide, James M Murphy.
      The necroptosis cell death pathway has been implicated in host defense and in the pathology of inflammatory diseases. While phosphorylation of the necroptotic effector pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) by the upstream protein kinase RIPK3 is a hallmark of pathway activation, the precise checkpoints in necroptosis signaling are still unclear. Here we have developed monobodies, synthetic binding proteins, that bind the N-terminal four-helix bundle (4HB) "killer" domain and neighboring first brace helix of human MLKL with nanomolar affinity. When expressed as genetically encoded reagents in cells, these monobodies potently block necroptotic cell death. However, they did not prevent MLKL recruitment to the "necrosome" and phosphorylation by RIPK3, nor the assembly of MLKL into oligomers, but did block MLKL translocation to membranes where activated MLKL normally disrupts membranes to kill cells. An X-ray crystal structure revealed a monobody-binding site centered on the α4 helix of the MLKL 4HB domain, which mutational analyses showed was crucial for reconstitution of necroptosis signaling. These data implicate the α4 helix of its 4HB domain as a crucial site for recruitment of adaptor proteins that mediate membrane translocation, distinct from known phospholipid binding sites.
    Keywords:  RIPK3; cell death; programmed necrosis; protein engineering; protein interactions
    DOI:  https://doi.org/10.1073/pnas.1919960117
  2. Cell Rep. 2020 Mar 31. pii: S2211-1247(20)30346-6. [Epub ahead of print]30(13): 4343-4354.e4
    Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection.
    Gregor Ebert, Sash Lopaticki, Matthew T O'Neill, Ryan W J Steel, Marcel Doerflinger, Pravin Rajasekaran, Annie S P Yang, Sara Erickson, Lisa Ioannidis, Philip Arandjelovic, Liana Mackiewicz, Cody Allison, John Silke, Marc Pellegrini, Justin A Boddey.
      Plasmodium sporozoites infect the liver and develop into exoerythrocytic merozoites that initiate blood-stage disease. The hepatocyte molecular pathways that permit or abrogate parasite replication and merozoite formation have not been thoroughly explored, and a deeper understanding may identify therapeutic strategies to mitigate malaria. Cellular inhibitor of apoptosis (cIAP) proteins regulate cell survival and are co-opted by intracellular pathogens to support development. Here, we show that cIAP1 levels are upregulated during Plasmodium liver infection and that genetic or pharmacological targeting of cIAPs using clinical-stage antagonists preferentially kills infected hepatocytes and promotes immunity. Using gene-targeted mice, the mechanism was defined as TNF-TNFR1-mediated apoptosis via caspases 3 and 8 to clear parasites. This study reveals the importance of cIAPs to Plasmodium infection and demonstrates that host-directed antimalarial drugs can eliminate liver parasites and induce immunity while likely providing a high barrier to resistance in the parasite.
    Keywords:  IAP antagonist; Plasmodium; SMAC mimetic; T cells; antibodies; birinapant; cIAP; immunity; inhibitor of apoptosis proteins; protection
    DOI:  https://doi.org/10.1016/j.celrep.2020.03.032
  3. Cells. 2020 Mar 20. pii: E764. [Epub ahead of print]9(3):
    On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function.
    Éva S Vanamee, Denise L Faustman.
      Tumor necrosis factor (TNF) superfamily ligands show diverse biological functions, such as the induction of apoptotic cell death or cell survival and proliferation, making them excellent therapeutic targets for cancer and autoimmunity. We review the latest literature on TNF receptor superfamily signaling with a focus on structure-function. Using combinatorics, we argue that receptors that cluster on the cell surface and are activated by membrane-bound ligands need to arrange in a highly ordered manner, as the probability of random ligand and receptor arrangements matching up for receptor activation is very low. A growing body of evidence indicates that antiparallel receptor dimers that sequester the ligand binding site cluster on the cell surface, forming a hexagonal lattice. Upon ligand binding, this arrangement puts the activated receptors at the right distance to accommodate the downstream signaling partners. The data also suggest that the same geometry is utilized regardless of receptor type. The unified model provides important clues about TNF receptor signaling and should aid the design of better therapies for cancer and various immune mediated diseases.
    Keywords:  TNFSF signaling; TRAIL; TRAIL receptors; antiparallel dimer; apoptosis; cancer; hexagonal lattice; receptor clustering
    DOI:  https://doi.org/10.3390/cells9030764
  4. FEBS J. 2020 Apr 01.
    Double agents of cell death: novel emerging functions of apoptotic regulators.
    Heather M Lamb.
      Apoptosis is a highly regulated form of cell death that is required for many homeostatic and pathological processes. Recently, alternative cell death pathways have emerged whose regulation is dependent on proteins with canonical functions in apoptosis. Dysregulation of apoptotic signaling frequently underlies the pathogenesis of many cancers, reinforcing the need to develop therapies that initiate alternative cell death processes. This review outlines the convergence points between apoptosis and other death pathways with the purpose of identifying novel strategies for the treatment of apoptosis-refractory cancers. Apoptosis proteins can play key roles in the initiation, regulation, and execution of non-apoptotic death processes that include necroptosis, autophagy, pyroptosis, mPTP-mediated necrosis and ferroptosis. Notably, recent evidence illustrates that dying cells can exhibit biochemical and molecular characteristics of more than one different type of regulated cell death. Thus, this review highlights the amazing complexity and interconnectivity of cell death processes and also raises the idea that a top-to-bottom approach to describing cell death mechanisms may be inadequate for fully understanding the means by which cells die.
    Keywords:  BCL-2; apoptosis; autophagy; cancer; caspase; ferroptosis; mPTP; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1111/febs.15308
  5. Int J Mol Sci. 2020 Mar 31. pii: E2412. [Epub ahead of print]21(7):
    Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis.
    Uris Ros, Lohans Pedrera, Ana J Garcia-Saez.
      Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation.
    Keywords:  inflammation; membrane permeabilization; pores; protein-lipid interactions; regulated necrosis
    DOI:  https://doi.org/10.3390/ijms21072412
  6. Commun Biol. 2020 Apr 03. 3(1): 163
    Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.
    Daisuke Oikawa, Yusuke Sato, Fumiaki Ohtake, Keidai Komakura, Kazuki Hanada, Koji Sugawara, Seigo Terawaki, Yukari Mizukami, Hoang T Phuong, Kiyosei Iio, Shingo Obika, Masaya Fukushi, Takashi Irie, Daisuke Tsuruta, Shinji Sakamoto, Keiji Tanaka, Yasushi Saeki, Shuya Fukai, Fuminori Tokunaga.
      The NF-κB and interferon antiviral signaling pathways play pivotal roles in inflammatory and innate immune responses. The LUBAC ubiquitin ligase complex, composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical NF-κB pathway through Met1-linked linear ubiquitination. We identified small-molecule chemical inhibitors of LUBAC, HOIPIN-1 and HOIPIN-8. Here we show that HOIPINs down-regulate not only the proinflammatory cytokine-induced canonical NF-κB pathway, but also various pathogen-associated molecular pattern-induced antiviral pathways. Structural analyses indicated that HOIPINs inhibit the RING-HECT-hybrid reaction in HOIP by modifying the active Cys885, and residues in the C-terminal LDD domain, such as Arg935 and Asp936, facilitate the binding of HOIPINs to LUBAC. HOIPINs effectively induce cell death in activated B cell-like diffuse large B cell lymphoma cells, and alleviate imiquimod-induced psoriasis in model mice. These results reveal the molecular and cellular bases of LUBAC inhibition by HOIPINs, and demonstrate their potential therapeutic uses.
    DOI:  https://doi.org/10.1038/s42003-020-0882-8
  7. Trends Pharmacol Sci. 2020 Mar 25. pii: S0165-6147(20)30059-6. [Epub ahead of print]
    Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality.
    Milka Kostic, Lyn H Jones.
      Small molecules continue to dominate drug discovery because of their ease of use, lower cost of manufacturing, and access to intracellular targets. However, despite these advantages, small molecules are more likely to fail in clinical trials compared with biologicals and their development remains limited to a small subset of disease-relevant 'druggable' targets. Targeted protein degradation has recently emerged as a novel pharmacological modality that promises to overcome small molecule limitations whilst retaining their key advantages. Here, we use a Strengths-Weaknesses-Opportunities-Threats (SWOT) framework to critically assess the current status of this rapidly evolving field. We expect that degrader molecules are only the beginning of a range of novel targeting modalities that hijack existing endogenous cellular machineries to chemically redirect biological targets and pathways. Therefore, this piece may offer a roadmap for enhancing development of both degraders and related modalities.
    Keywords:  degrader molecules; small molecule drug discovery; targeted protein degradation; undruggable targets
    DOI:  https://doi.org/10.1016/j.tips.2020.02.006
  8. Trends Immunol. 2020 Mar 30. pii: S1471-4906(20)30039-9. [Epub ahead of print]
    A20 and Cell Death-driven Inflammation.
    Dario Priem, Geert van Loo, Mathieu J M Bertrand.
      A20 is a potent anti-inflammatory molecule, and mutations in TNFAIP3, the gene encoding A20, are associated with a wide panel of inflammatory pathologies, both in human and mouse. The anti-inflammatory properties of A20 are commonly attributed to its ability to suppress inflammatory NF-κB signaling by functioning as a ubiquitin-editing enzyme. However, A20 also protects cells from death, independently of NF-κB regulation, and recent work has demonstrated that cell death may drive some of the inflammatory conditions caused by A20 deficiency. Adding to the fact that the protective role of A20 does not primarily rely on its catalytic activities, these findings shed new light on A20 biology.
    DOI:  https://doi.org/10.1016/j.it.2020.03.001
  9. BMC Mol Cell Biol. 2020 Mar 30. 21(1): 21
    Robust high-throughput assays to assess discrete steps in ubiquitination and related cascades.
    Gabriel Fenteany, Paras Gaur, Gaurav Sharma, Lajos Pintér, Ernő Kiss, Lajos Haracska.
       BACKGROUND: Ubiquitination and ubiquitin-like protein post-translational modifications play an enormous number of roles in cellular processes. These modifications are constituted of multistep reaction cascades. Readily implementable and robust methods to evaluate each step of the overall process, while presently limited, are critical to the understanding and modulation of the reaction sequence at any desired level, both in terms of basic research and potential therapeutic drug discovery and development.
    RESULTS: We developed multiple robust and reliable high-throughput assays to interrogate each of the sequential discrete steps in the reaction cascade leading to protein ubiquitination. As models for the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, the E3 ubiquitin ligase, and their ultimate substrate of ubiquitination in a cascade, we examined Uba1, Rad6, Rad18, and proliferating cell nuclear antigen (PCNA), respectively, in reconstituted systems. Identification of inhibitors of this pathway holds promise in cancer therapy since PCNA ubiquitination plays a central role in DNA damage tolerance and resulting mutagenesis. The luminescence-based assays we developed allow for the quantitative determination of the degree of formation of ubiquitin thioester conjugate intermediates with both E1 and E2 proteins, autoubiquitination of the E3 protein involved, and ubiquitination of the final substrate. Thus, all covalent adducts along the cascade can be individually probed. We tested previously identified inhibitors of this ubiquitination cascade, finding generally good correspondence between compound potency trends determined by more traditional low-throughput methods and the present high-throughput ones.
    CONCLUSIONS: These approaches are readily adaptable to other E1, E2, and E3 systems, and their substrates in both ubiquitination and ubiquitin-like post-translational modification cascades.
    Keywords:  E1 ubiquitin-conjugating enzymes; E2 ubiquitin-conjugating enzymes; E3 ubiquitin ligases; High-throughput screening; Post-translational modifications; Step-specific assays and evaluation; Ubiquitin-like proteins; Ubiquitination
    DOI:  https://doi.org/10.1186/s12860-020-00262-5
  10. Cell Death Differ. 2020 Mar 30.
    OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer.
    Rune Busk Damgaard, Helen E Jolin, Michael E D Allison, Susan E Davies, Hannah L Titheradge, Andrew N J McKenzie, David Komander.
      Methionine-1 (M1)-linked polyubiquitin chains conjugated by the linear ubiquitin chain assembly complex (LUBAC) control NF-κB activation, immune homoeostasis, and prevents tumour necrosis factor (TNF)-induced cell death. The deubiquitinase OTULIN negatively regulates M1-linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. However, the cellular pathways and physiological functions controlled by OTULIN remain poorly understood. Here, we show that OTULIN prevents development of liver disease in mice and humans. In an ORAS patient, OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10-13 months of age. Similarly, liver-specific deletion of OTULIN in mice leads to neonatally onset steatosis and hepatitis, akin to the ORAS patient. OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver. In mice, steatosis progresses to steatohepatitis, fibrosis and pre-malignant tumour formation by 8 weeks of age, and by the age of 7-12 months the phenotype has advanced to malignant hepatocellular carcinoma. Surprisingly, the pathology in OTULIN-deficient livers is independent of TNFR1 signalling. Instead, we find that steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation, and inhibition of mTOR by rapamycin administration significantly reduces the liver pathology. Collectively, our results reveal that OTULIN is critical for maintaining liver homoeostasis and suggest that M1-linked polyubiquitin chains may play a role in regulation of mTOR signalling and metabolism in the liver.
    DOI:  https://doi.org/10.1038/s41418-020-0532-1
  11. Cell Death Dis. 2020 Mar 31. 11(3): 212
    TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice.
    Franziska Wandrer, Stephanie Liebig, Silke Marhenke, Arndt Vogel, Katharina John, Michael P Manns, Andreas Teufel, Timo Itzel, Thomas Longerich, Olaf Maier, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Klaus Schulze-Osthoff, Heike Bantel.
      Non-alcoholic fatty liver disease (NAFLD) shows an increasing prevalence and is associated with the development of liver fibrosis and cirrhosis as the major risk factors of liver-related mortality in this disease. The therapeutic possibilities are limited and restricted to life style intervention, since specific drugs for NAFLD are unavailable so far. TNFα has been implicated as a major pathogenic driver of NAFLD. TNFα-mediated liver injury occurs mainly via TNF-receptor-1 (TNFR1) signaling, whereas TNFR2 mediates protective pathways. In this study, we analyzed the therapeutic effects of a novel antibody, which selectively inhibits TNFR1 while retaining protective TNFR2 signaling in a high-fat diet (HFD) mouse model of NAFLD. Mice were fed with HFD for 32 weeks and treated with anti-TNFR1-antibody or control-antibody for the last 8 weeks. We then investigated the mechanisms of TNFR1 inhibition on liver steatosis, inflammatory liver injury, insulin resistance and fibrosis. Compared to control-antibody treatment, TNFR1 inhibition significantly reduced liver steatosis and triglyceride content, which was accompanied by reduced expression and activation of the transcription factor SREBP1 and downstream target genes of lipogenesis. Furthermore, inhibition of TNFR1 resulted in reduced activation of the MAP kinase MKK7 and its downstream target JNK, which was associated with significant improvement of insulin resistance. Apoptotic liver injury, NAFLD activity and alanine aminotransferase (ALT) levels, as well as liver fibrosis significantly decreased by anti-TNFR1 compared to control-antibody treatment. Thus, our results suggest selective TNFR1 inhibition as a promising approach for NAFLD treatment.
    DOI:  https://doi.org/10.1038/s41419-020-2411-6
  12. Acta Pharmacol Sin. 2020 Apr 02.
    RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells.
    Xue-Lian Zheng, Jiao-Jiao Yang, Yan-Yun Wang, Qin Li, Ya-Ping Song, Min Su, Jin-Ke Li, Lin Zhang, Zhi-Ping Li, Bin Zhou, Yong Lin.
      Receptor-interacting protein 1 (RIP1, also known as RIPK1) is not only a tumor-promoting factor in several cancers but also mediates either apoptosis or necroptosis in certain circumstances. In this study we investigated what role RIP1 plays in human ovarian cancer cells. We showed that knockout (KO) of RIP1 substantially suppressed cell proliferation, accompanied by the G2/M checkpoint arrest in two human ovarian cancer cell lines SKOV3 and A2780. On the other hand, RIP1 KO remarkably attenuated cisplatin-induced cytotoxicity, which was associated with reduction of the apoptosis markers PARP cleavage and the necroptosis marker phospho-MLKL. We found that RIP1 KO suppressed cisplatin-induced ROS accumulation in both SKOV3 and A2780 cells. ROS scavenger BHA, apoptosis inhibitor Z-VAD or necroptosis inhibitor NSA could effectively suppress cisplatin's cytotoxicity in the control cells, suggesting that ROS-mediated apoptosis and necroptosis were involved in cisplatin-induced cell death. In addition, blocking necroptosis with MLKL siRNA effectively attenuated cisplatin-induced cytotoxicity. In human ovarian cancer A2780 cell line xenograft nude mice, RIP1 KO not only significantly suppressed the tumor growth but also greatly attenuated cisplatin's anticancer activity. Our results demonstrate a dual role of RIP1 in human ovarian cancer: it acts as either a tumor-promoting factor to promote cancer cell proliferation or a tumor-suppressing factor to facilitate anticancer effects of chemotherapeutics such as cisplatin.
    Keywords:  BHA; NSA; RIP1; RIPK1; ROS; Z-VAD; apoptosis; cisplatin; necroptosis; ovarian cancer; proliferation; taxol
    DOI:  https://doi.org/10.1038/s41401-019-0340-7
  13. Cell Mol Biol Lett. 2020 ;25 23
    The role of phosphatidylserine recognition receptors in multiple biological functions.
    Mehri Bemani Naeini, Vanessa Bianconi, Matteo Pirro, Amirhossein Sahebkar.
      Apoptotic cells are rapidly engulfed and degraded by phagocytes through efferocytosis. Efferocytosis is a highly regulated process. It is triggered upon the activation of caspase-dependent apoptosis, which in turn promotes the expression of "eat me" signals on the surface of dying cells and the release of soluble "find me" signals for the recruitment of phagocytes. To date, many "eat me" signals have been recognized, including phosphatidylserine (PS), intercellular adhesion molecule-3, carbohydrates (e.g., amino sugars, mannose) and calreticulin. Among them, PS is the most studied one. PS recognition receptors are different functionally active receptors expressed by phagocytes. Various PS recognition receptors with different structure, cell type expression, and ability to bind to PS have been recognized. Although PS recognition receptors do not fall into a single classification or family of proteins due to their structural differences, they all share the common ability to activate downstream signaling pathways leading to the production of anti-inflammatory mediators. In this review, available evidence regarding molecular mechanisms underlying PS recognition receptor-regulated clearance of apoptotic cells is discussed. In addition, some efferocytosis-independent biological functions of PS recognition receptors are reviewed.
    Keywords:  Apoptosis; Efferocytosis; Macrophage; Phosphatidylethanolamine; Phosphatidylserine; Receptor
    DOI:  https://doi.org/10.1186/s11658-020-00214-z
  14. Cancer Discov. 2020 Apr;10(4): 492-494
    Not So FASt: Tumor Cells Resisting Death Drive CAR T-cell Dysfunction.
    Michael R Green, Sattva S Neelapu.
      In this issue, Singh and colleagues describe a novel tumor-intrinsic mechanism of resistance to chimericantigen receptor (CAR) T-cell therapy targeting CD19 in B-cell malignancies. They show that reduced expression of death receptor genes in the tumors mediates resistance to killing by CAR T cells, leads to progressive CAR T-cell dysfunction, and is associated with unfavorable clinical outcome in patients.See related article by Singh et al., p. 552.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0037
  15. Leukemia. 2020 Apr 01.
    Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways.
    Teru Hideshima, Daisuke Ogiya, Jiye Liu, Takeshi Harada, Keiji Kurata, Jooeun Bae, Walter Massefski, Kenneth C Anderson.
      Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide show remarkable antitumor activity in multiple myeloma (MM) via directly inhibiting MM-cell growth in the bone marrow (BM) microenvironment and promoting immune effector cell function. They are known to bind to the ubiquitin 3 ligase CRBN complex and thereby triggering degradation of IKZF1/3. In this study, we demonstrate that IMiDs also directly bind and activate zeta-chain-associated protein kinase-70 (Zap-70) via its tyrosine residue phosphorylation in T cells. IMiDs also triggered phosphorylation of Zap-70 in natural killer (NK) cells. Importantly, increased granzyme-B (GZM-B) expression and NK-cell activity triggered by IMiDs is associated with Zap-70 activation and inhibited by Zap-70 knockdown (KD), independent of CRBN. We also demonstrate a second mechanism whereby IMiDs trigger GZM-B and NK cytotoxicity which is CRBN and IKZF3 mediated, and inhibited or enhanced by KD of CRBN or IKZF3, respectively, independent of Zap-70. Our studies therefore show that IMiDs can enhance NK and T-cell cytotoxicity in (1) ZAP-70-mediated CRBN independent, as well as (2) CRBN-mediated ZAP-70 independent mechanisms; and provide the framework for developing novel therapeutics to activate Zap-70 and thereby enhance T and NK anti-MM cytotoxicity.
    DOI:  https://doi.org/10.1038/s41375-020-0809-x
  16. J Pathol. 2020 Mar 28.
    Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut.
    Nadine Mikuda, Ruth Schmidt-Ullrich, Eva Kärgel, Laura Golusda, Jana Wolf, Uta E Höpken, Claus Scheidereit, Anja A Kühl, Marina Kolesnichenko.
      The IκB-Kinase (IKK)-NF-κB signalling pathway plays a multifaceted role in inflammatory bowel disease (IBD): on the one hand, it protects from apoptosis; on the other, it activates transcription of numerous inflammatory cytokines and chemokines. Although several murine models of IBD rely on disruption of IKK-NF-κB signalling, these involve either knockouts of a single family-member of NF-κB, or of upstream kinases that are known to have additional, NF-κB-independent, functions. This has made the distinct contribution of NF-κB to homeostasis in intestinal epithelium cells difficult to assess. To examine the role of constitutive NF-κB activation in intestinal epithelial cells, we generated a mouse model with a tissue-specific knockout of the direct inhibitor of NF-κB, Nfkbia/IκBα. We demonstrate that constitutive activation of NF-κB in intestinal epithelial cells induces several hallmarks of IBD including increased apoptosis, mucosal inflammation in both the small intestine and the colon, crypt hyperplasia, and depletion of Paneth cells, concomitant with aberrant Wnt signalling. To determine which NF-κB-driven phenotypes are cell-intrinsic, and which are extrinsic and thus require the immune compartment, we established a long-term organoid culture. Constitutive NF-κB promoted stem-cell proliferation, mis-localisation of Paneth cells, and sensitisation of intestinal epithelial cells to apoptosis in a cell-intrinsic manner. Increased number of stem cells was accompanied by a net increase in Wnt activity in organoids. Because aberrant Wnt signalling is associated with increased risk of cancer in IBD patients and because NFKBIA has recently emerged as a risk locus for IBD, our findings have critical implications for the clinic. In a context of constitutive NF-κB, our findings imply that general anti-inflammatory or immunosuppressive therapies should be supplemented with direct targeting of NF-κB within the epithelial compartment in order to attenuate apoptosis, inflammation, and hyperproliferation. This article is protected by copyright. All rights reserved.
    Keywords:  Inflammatory bowel disease; NF-κB; Wnt; animal model; crypts; inflammation; intestinal organoids; precision medicine; stem cells
    DOI:  https://doi.org/10.1002/path.5437
  17. Curr Opin Chem Biol. 2020 Feb;pii: S1367-5931(20)30026-0. [Epub ahead of print]54 A1-A4
    Editorial Overview: Tracking the ties that bind: Emerging technologies to profile biomolecular interactions in native environments.
    Raymond E Moellering.
      
    DOI:  https://doi.org/10.1016/j.cbpa.2020.03.001
  18. Infect Immun. 2020 Mar 30. pii: IAI.00898-19. [Epub ahead of print]
    NOD1 and NOD2 activation by diverse stimuli: a possible role for sensing pathogen-induced ER stress.
    Sharon K Kuss-Duerkop, A Marijke Keestra-Gounder.
      Prompt recognition of microbes by cells is critical to eliminate invading pathogens. Some cell-associated pattern recognition receptors (PRRs) recognize and respond to microbial ligands. However, others can respond to cellular perturbations, such as damage-associated molecular patterns (DAMPs). Nucleotide oligomerization domain 1 and 2 (NOD1, NOD2) are PRRs that recognize and respond to multiple stimuli of microbial and cellular origin, such as bacterial peptidoglycan, viral infections, parasitic infections, activated Rho GTPases and endoplasmic reticulum (ER) stress. How NOD1/2 are stimulated by such diverse stimuli is not fully understood but may partly rely on cellular changes during infection that result in ER stress. NOD1/2 are ER stress sensors that facilitate pro-inflammatory responses for pathogen clearance; thus, NOD1/2 may help mount broad anti-microbial responses through detection of ER stress, which is often induced during a variety of infections. Some pathogens may subvert this response to promote infection through manipulation of NOD1/2 responses to ER stress that lead to apoptosis. Herein, we review NOD1/2 stimuli and cellular responses. Furthermore, we discuss pathogen-induced ER stress and how it might potentiate NOD1/2 signaling.
    DOI:  https://doi.org/10.1128/IAI.00898-19
  19. Nat Rev Cancer. 2020 Mar 31.
    Understanding cachexia in the context of metastatic progression.
    Anup K Biswas, Swarnali Acharyya.
      Tumours reprogram host physiology, metabolism and immune responses during cancer progression. The release of soluble factors, exosomes and metabolites from tumours leads to systemic changes in distant organs, where cancer cells metastasize and grow. These tumour-derived circulating factors also profoundly impact tissues that are rarely inhabited by metastatic cancer cells such as skeletal muscle and adipose tissue. In fact, the majority of patients with metastatic cancer develop a debilitating muscle-wasting syndrome, known as cachexia, that is associated with decreased tolerance to antineoplastic therapy, poor prognosis and accelerated death, with no approved treatments. In this Perspective, we discuss the development of cachexia in the context of metastatic progression. We briefly discuss how circulating factors either directly or indirectly promote cachexia development and examine how signals from the metastatic process can trigger and amplify this process. Finally, we highlight promising therapeutic opportunities for targeting cachexia in the context of metastatic cancers.
    DOI:  https://doi.org/10.1038/s41568-020-0251-4
  20. Curr Opin Cell Biol. 2020 Mar 29. pii: S0955-0674(20)30034-X. [Epub ahead of print]65 78-85
    "Make way": Pathogen exploitation of membrane traffic.
    Julia Noack, Shaeri Mukherjee.
      Intracellular pathogens have evolved numerous strategies to manipulate their host cells to survive and replicate in a hostile environment. They often exploit membrane trafficking pathways to enter the cell, establish a replicative niche, avoid degradation and immune response, acquire nutrients and lastly, egress. Recent studies on membrane trafficking exploitation by intracellular pathogens have led to the discovery of novel and fascinating cell biology, including a noncanonical mechanism of ubiquitination and a novel mitophagy receptor. Thus, studying how pathogens target host cell membrane trafficking pathways is not only important for the development of new therapeutics, but also helps understanding fundamental mechanisms of cell biology.
    Keywords:  Autophagy; Flavivirus; Host-pathogen interactions; Legionella; Membrane trafficking; Secretory pathway
    DOI:  https://doi.org/10.1016/j.ceb.2020.02.011
  21. Cancers (Basel). 2020 Mar 20. pii: E739. [Epub ahead of print]12(3):
    The Multifactorial Role of PARP-1 in Tumor Microenvironment.
    Juan Manuel Martí, Mónica Fernández-Cortés, Santiago Serrano-Sáenz, Esteban Zamudio-Martinez, Daniel Delgado-Bellido, Angel Garcia-Diaz, Francisco Javier Oliver.
      Poly(ADP-ribose) polymerases (PARPs), represent a family of 17 proteins implicated in a variety of cell functions; some of them possess the enzymatic ability to synthesize and attach poly (ADP-ribose) (also known as PAR) to different protein substrates by a post-translational modification; PARPs are key components in the cellular response to stress with consequences for different physiological and pathological events, especially during neoplasia. In recent years, using PARP inhibitors as antitumor agents has raised new challenges in understanding their role in tumor biology. Notably, the function of PARPs and PAR in the dynamic of tumor microenvironment is only starting to be understood. In this review, we summarized the conclusions arising from recent studies on the interaction between PARPs, PAR and key features of tumor microenvironment such as hypoxia, autophagy, tumor initiating cells, angiogenesis and cancer-associated immune response.
    Keywords:  PARP inhibitors; PARPs; PARylation; Tumor microenvironment; autophagy; hypoxia
    DOI:  https://doi.org/10.3390/cancers12030739
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