bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒05‒10
twenty-nine papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research

  1. Immunity. 2020 Apr 22. pii: S1074-7613(20)30160-6. [Epub ahead of print]
    Schwarzer R, Jiao H, Wachsmuth L, Tresch A, Pasparakis M.
      Pathways controlling intestinal epithelial cell (IEC) death regulate gut immune homeostasis and contribute to the pathogenesis of inflammatory bowel diseases. Here, we show that caspase-8 and its adapter FADD act in IECs to regulate intestinal inflammation downstream of Z-DNA binding protein 1 (ZBP1)- and tumor necrosis factor receptor-1 (TNFR1)-mediated receptor interacting protein kinase 1 (RIPK1) and RIPK3 signaling. Mice with IEC-specific FADD or caspase-8 deficiency developed colitis dependent on mixed lineage kinase-like (MLKL)-mediated epithelial cell necroptosis. However, MLKL deficiency fully prevented ileitis caused by epithelial caspase-8 ablation, but only partially ameliorated ileitis in mice lacking FADD in IECs. Our genetic studies revealed that caspase-8 and gasdermin-D (GSDMD) were both required for the development of MLKL-independent ileitis in mice with epithelial FADD deficiency. Therefore, FADD prevents intestinal inflammation downstream of ZBP1 and TNFR1 by inhibiting both MLKL-induced necroptosis and caspase-8-GSDMD-dependent pyroptosis-like death of epithelial cells.
    Keywords:  Caspase-8; FADD; GSDMD; ZBP1; apoptosis; cell death; inflammation; inflammatory bowel disease; necroptosis; pyroptosis
  2. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(19)30127-3. [Epub ahead of print]353 211-253
    Imre G.
      Apoptosis, necroptosis and pyroptosis represent three distinct types of regulated cell death forms, which play significant roles in response to viral and bacterial infections. Whereas apoptosis is characterized by cell shrinkage, nuclear condensation, bleb formation and retained membrane integrity, necroptosis and pyroptosis exhibit osmotic imbalance driven cytoplasmic swelling and early membrane damage. These three cell death forms exert distinct immune stimulatory potential. The caspase driven apoptotic cell demise is considered in many circumstances as anti-inflammatory, whereas the two lytic cell death modalities can efficiently trigger immune response by releasing damage associated molecular patterns to the extracellular space. The relevance of these cell death modalities in infections can be best demonstrated by the presence of viral proteins that directly interfere with cell death pathways. Conversely, some pathogens hijack the cell death signaling routes to initiate a targeted attack against the immune cells of the host, and extracellular bacteria can benefit from the destruction of intact extracellular barriers upon cell death induction. The complexity and the crosstalk between these cell death modalities reflect a continuous evolutionary race between pathogens and host. This chapter discusses the current advances in the research of cell death signaling with regard to viral and bacterial infections and describes the network of the cell death initiating molecular mechanisms that selectively recognize pathogen associated molecular patterns.
    Keywords:  Apoptosis; Bacteria; Caspases; Cell death; Infection; Inflammasome; Necroptosis; Necrosome; Pyroptosis; Virus
  3. Proc Natl Acad Sci U S A. 2020 May 04. pii: 202003043. [Epub ahead of print]
    Oh JH, Hyun JY, Chen SJ, Varshavsky A.
      The Arg/N-degron pathway targets proteins for degradation by recognizing their N-terminal (Nt) residues. If a substrate bears, for example, Nt-Asn, its targeting involves deamidation of Nt-Asn, arginylation of resulting Nt-Asp, binding of resulting (conjugated) Nt-Arg to the UBR1-RAD6 E3-E2 ubiquitin ligase, ligase-mediated synthesis of a substrate-linked polyubiquitin chain, its capture by the proteasome, and substrate's degradation. We discovered that the human Nt-Asn-specific Nt-amidase NTAN1, Nt-Gln-specific Nt-amidase NTAQ1, arginyltransferase ATE1, and the ubiquitin ligase UBR1-UBE2A/B (or UBR2-UBE2A/B) form a complex in which NTAN1 Nt-amidase binds to NTAQ1, ATE1, and UBR1/UBR2. In addition, NTAQ1 Nt-amidase and ATE1 arginyltransferase also bind to UBR1/UBR2. In the yeast Saccharomyces cerevisiae, the Nt-amidase, arginyltransferase, and the double-E3 ubiquitin ligase UBR1-RAD6/UFD4-UBC4/5 are shown to form an analogous targeting complex. These complexes may enable substrate channeling, in which a substrate bearing, for example, Nt-Asn, would be captured by a complex-bound Nt-amidase, followed by sequential Nt modifications of the substrate and its polyubiquitylation at an internal Lys residue without substrate's dissociation into the bulk solution. At least in yeast, the UBR1/UFD4 ubiquitin ligase interacts with the 26S proteasome, suggesting an even larger Arg/N-degron-targeting complex that contains the proteasome as well. In addition, specific features of protein-sized Arg/N-degron substrates, including their partly sequential and partly nonsequential enzymatic modifications, led us to a verifiable concept termed "superchanneling." In superchanneling, the synthesis of a substrate-linked poly-Ub chain can occur not only after a substrate's sequential Nt modifications, but also before them, through a skipping of either some or all of these modifications within a targeting complex.
    Keywords:  channeling; degradation; degron; superchanneling; ubiquitin
  4. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(19)30125-X. [Epub ahead of print]353 31-82
    Dionísio PA, Amaral JD, Rodrigues CMP.
      Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL), being also generally dependent on RIP1 kinase activity. Necroptosis can be recruited during pathological conditions, usually following the activation of death receptors under specific cellular contexts. In this regard, necroptosis has been implicated in the pathogenesis of multiple disorders, including acute and chronic neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, and multiple sclerosis. Here, we summarize the molecular mechanisms regulating the induction of necroptosis and downstream effectors of this form of cell death, besides exploring non-necroptotic roles for necroptosis-related proteins that may impact on alternative cell death pathways and inflammatory mechanisms in disease. Finally, we outline the recent evidence implicating necroptosis in neurodegenerative conditions and the emerging therapeutic perspectives targeting necroptosis in these diseases.
    Keywords:  MLKL; Mitochondria; Necroptosis; Neurodegenerative diseases; RIP1/RIPK1; RIP3/RIPK3; ROS; TNF-α
  5. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(19)30128-5. [Epub ahead of print]353 1-29
    Park H, Kam TI, Dawson TM, Dawson VL.
      Disruption of cellular functions with aging-induced accumulation of neuronal stressors causes cell death which is a common feature of neurodegenerative diseases. Studies in a variety of neurodegenerative disease models demonstrate that poly (ADP-ribose) (PAR)-dependent cell death, also named parthanatos, is responsible for neuronal loss in neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Parthanatos has distinct features that differ from caspase-dependent apoptosis, necrosis or autophagic cell death. Parthanatos can be triggered by the accumulation of PAR due to overactivation of PAR polymerase-1 (PARP-1). Excess PAR, induces the mitochondrial release apoptosis-inducing factor (AIF), which binds to macrophage migration inhibitory factor (MIF) carrying MIF into the nucleus where it cleaves genomic DNA into large fragments. In this review, we will discuss the molecular mechanisms of parthanatos and their role in neurodegenerative diseases. Furthermore, we will discuss promising therapeutic interventions within the pathological PAR signaling cascade that could be designed to halt the progression of neurodegeneration.
    Keywords:  AIF; Cell death; MIF; Neurodegenerative disease; PAR; PARP-1; Parthanatos; Poly (ADP-ribose)
  6. Cells. 2020 Apr 30. pii: E1118. [Epub ahead of print]9(5):
    Dumétier B, Zadoroznyj A, Dubrez L.
      Over the last decade, the E3-ubiquitine ligases from IAP (Inhibitor of Apoptosis) family have emerged as potent regulators of immune response. In immune cells, they control signaling pathways driving differentiation and inflammation in response to stimulation of tumor necrosis factor receptor (TNFR) family, pattern-recognition receptors (PRRs), and some cytokine receptors. They are able to control the activity, the cellular fate, or the stability of actors of signaling pathways, acting at different levels from components of receptor-associated multiprotein complexes to signaling effectors and transcription factors, as well as cytoskeleton regulators. Much less is known about ubiquitination substrates involved in non-immune signaling pathways. This review aimed to present IAP ubiquitination substrates and the role of IAP-mediated ubiquitination in regulating signaling pathways.
    Keywords:  IAP; cell signaling; inflammation; ubiquitination
  7. Blood. 2020 May 08. pii: blood.2019003105. [Epub ahead of print]
    Grants JM, Wegrzyn-Woltosz J, Hui T, O'Neill K, Shadbolt M, Knapp DJHF, Parker JD, Deng D, Gopal A, Docking TR, Fuller M, Li J, Boldin M, Eaves CJ, Hirst M, Karsan A.
      Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging ("inflammaging") has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. Here, we identify loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a-null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a-/- myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a-/-HSC function and subpopulation structure, and reduced the incidence of hematological malignancy in miR‑146a-/-mice. miR-146a-/- HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR‑146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.
  8. Int J Mol Sci. 2020 May 05. pii: E3263. [Epub ahead of print]21(9):
    Cudrici C, Deuitch N, Aksentijevich I.
      Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients' leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options.
    Keywords:  AA amyloidosis; IL-1inhibitors; TNF inhibitors; TNFR1; autoinflammatory disorders; misfolding disease; tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
  9. Cell Death Dis. 2020 May 04. 11(5): 305
    Wu YH, Chou TF, Young L, Hsieh FY, Pan HY, Mo ST, Brown SB, Chen RH, Kimchi A, Lai MZ.
      Death-associated protein kinase 1 (DAPK1, DAPk, DAPK) is known for its involvement in apoptosis and autophagy-associated cell death. Here, we identified an unexpected function of DAPK1 in suppressing necroptosis. DAPK1-deficiency renders macrophages and dendritic cells susceptible to necroptotic death. We also observed an inhibitory role for DAPK1 in necroptosis in HT-29 cells, since knockdown or knockout of DAPK1 in such cells increased their sensitivity to necroptosis. Increased necroptosis was associated with enhanced formation of the RIPK1-RIPK3-MLKL complex in these DAPK1-deficient cells. We further found that DAPK1-deficiency led to decreased MAPK activated kinase 2 (MK2) activation and reduced RIPK1 S321 phosphorylation, with this latter representing a critical step controlling necrosome formation. Most TNF signaling pathways, including ERK, JNK, and AKT, were not regulated by DAPK. In contrast, DAPK bound p38 MAPK and selectively promoted p38 MAPK activation, resulting in enhanced MK2 phosphorylation. Our results reveal a novel role for DAPK1 in inhibiting necroptosis and illustrate an unexpected selectivity for DAPK1 in promoting p38 MAPK-MK2 activation. Importantly, our study suggests that modulation of necroptosis and p38/MK2-mediated inflammation may be achieved by targeting DAPK1.
  10. Mol Med. 2020 May 07. 26(1): 42
    Andersson U, Ottestad W, Tracey KJ.
      BACKGROUND: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.CONCLUSION: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.
    Keywords:  ARDS; COVID-19; HMGB1; Influenza; Pathogenesis; Pneumonia; RAGE; SARS-CoV-2; TLR4; Therapy
  11. Structure. 2020 May 05. pii: S0969-2126(20)30134-9. [Epub ahead of print]28(5): 489-491
    Roelofs J.
      In this issue of Structure, Lu et al. (2020) describe an NMR-based study showing the proteasome ubiquitin receptor hRpn13 bound to an extended conformation of K48-diubiquitin that is different from previously described structures of K48-diubiquitin. Observed dynamic binding properties suggest an ability of substrates to hop between proteasome ubiquitin receptors.
  12. J Am Acad Dermatol. 2020 Apr 28. pii: S0190-9622(20)30721-0. [Epub ahead of print]
    Ellis S, Vierra AT, Millsop JW, Lacouture ME, Kiuru M.
      Antineoplastic agents that utilize the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death ligand 1 (PD-L1), show improved and sustained responses in cancer patients. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.
    Keywords:  CTLA-4; PD-L1; PD1; adverse event; atezolizumab; avelumab; bullous pemphigoid; checkpoint inhibitor; cutaneous; durvalumab; immunotherapy; ipilimumab; lichenoid dermatitis; nivolumab; pembrolizumab; rash; skin; toxicity
  13. Oncoimmunology. 2020 ;9(1): 1746148
    Song M, Wang C, Wang H, Zhang T, Li J, Benezra R, Chouchane L, Sun YH, Cui XG, Ma X.
      UBR5 is a nuclear phosphoprotein of obscure functions. Clinical analyses reveal that UBR5 amplifications and overexpression occur in over 20% cases of human breast cancers. Breast cancer patients carrying UBR5 genetic lesions with overexpression have significantly reduced survival. Experimental work in vitro and in vivo demonstrates that UBR5, functioning as an oncoprotein, plays a profound role in breast cancer growth and metastasis. UBR5 drives tumor growth largely through paracrine interactions with the immune system, particularly through inhibiting the cytotoxic response mediated by CD8+ T lymphocytes, whereas it facilitates metastasis in a tumor cell-autonomous manner via its transcriptional control of key regulators of the epithelial-mesenchymal transition, ID1 and ID3. Furthermore, simultaneous targeting of UBR5 and PD-L1 yields strong therapeutic benefit to tumor-bearing hosts. This work significantly expands our scarce understanding of the pathophysiology and immunobiology of a fundamentally important molecule and has strong implications for the development of novel immunotherapy to treat highly aggressive breast cancers that resist conventional treatment.
    Keywords:  E3 ligase; UBR5; breast cancer; immunotherapy; metastasis
  14. Front Immunol. 2020 ;11 567
    Mi Z, Liu H, Zhang F.
      Leprosy, a disease caused by the intracellular parasite Mycobacterium leprae or Mycobacterium lepromatosis, has affected humans for more than 4,000 years and is a stigmatized disease even now. Since clinical manifestations of leprosy patients present as an immune-related spectrum, leprosy is regarded as an ideal model for studying the interaction between host immune response and infection; in fact, the landscape of leprosy immune responses has been extensively investigated. Meanwhile, leprosy is to some extent a genetic disease because the genetic factors of hosts have long been considered major contributors to this disease. Many immune-related genes have been discovered to be associated with leprosy. However, immunological and genetic findings have rarely been studied and discussed together, and as a result, the effects of gene variants on leprosy immune responses and the molecular mechanisms of leprosy pathogenesis are largely unknown. In this context, we summarized advances in both the immunology and genetics of leprosy and discussed the perspective of the combination of immunological and genetic approaches in studying the molecular mechanism of leprosy pathogenesis. In our opinion, the integrating of immunological and genetic approaches in the future may be promising to elucidate the molecular mechanism of leprosy onset and how leprosy develops into different types of leprosy.
    Keywords:  adaptive immunity; genetic association; innate immunity; leprosy; variant
  15. Curr Opin Cell Biol. 2020 May 01. pii: S0955-0674(20)30045-4. [Epub ahead of print]66 1-10
    Wittmann T, Dema A, van Haren J.
      Cell biology is moving from observing molecules to controlling them in real time, a critical step towards a mechanistic understanding of how cells work. Initially developed from light-gated ion channels to control neuron activity, optogenetics now describes any genetically encoded protein system designed to accomplish specific light-mediated tasks. Recent photosensitive switches use many ingenious designs that bring spatial and temporal control within reach for almost any protein or pathway of interest. This next generation optogenetics includes light-controlled protein-protein interactions and shape-shifting photosensors, which in combination with live microscopy enable acute modulation and analysis of dynamic protein functions in living cells. We provide a brief overview of various types of optogenetic switches. We then discuss how diverse approaches have been used to control cytoskeleton dynamics with light through Rho GTPase signaling, microtubule and actin assembly, mitotic spindle positioning and intracellular transport and highlight advantages and limitations of different experimental strategies.
    Keywords:  Actin; Cell dynamics; Cry2; Cytoskeleton dynamics; LOV2; Light; Microscopy; Microtubule; Motor proteins; Optogenetics; Photoactivation; PhyB; Rho GTPase; VVD
  16. Clin Infect Dis. 2020 May 08. pii: ciaa546. [Epub ahead of print]
    Grassin-Delyle S, Salvator H, Brollo M, Catherinot E, Sage E, Couderc LJ, Naline E, Devillier P.
      On human lung parenchymal explants, chloroquine concentration clinically achievable in the lung (100 μM) inhibited the lipopolysaccharide-induced release of TNF-α (by 76%), IL-6 (by 68%), CCL2 (by 72%) and CCL3 (by 67%). Beside its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses.
    Keywords:  chemokine; chloroquine; interleukin-6; lipopolysaccharide; lung explant; tumour necrosis factor-alpha
  17. Ann Rheum Dis. 2020 May 07. pii: annrheumdis-2020-217163. [Epub ahead of print]
    Kerschbaumer A, Smolen JS, Dougados M, de Wit M, Primdahl J, McInnes I, van der Heijde D, Baraliakos X, Falzon L, Gossec L.
      OBJECTIVE: To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA).METHODS: This is a systematic literature research of 2015-2018 publications on all DMARDs in patients with PsA, searching Medline, Embase and the Cochrane Library. Efficacy was assessed in randomised controlled trials. For safety, cohort studies, case-control studies and long-term extensions (LTEs) were analysed.
    RESULTS: 56 publications (efficacy: n=33; safety n=23) were analysed. The articles were on tumour necrosis factor (TNF) inhibitors (n=6; golimumab, etanercept and biosimilars), interleukin (IL)-17A inhibitors (n=10; ixekizumab, secukinumab), IL-23-p19 inhibitors (n=2; guselkumab, risankizumab), clazakizumab (IL-6 inhibitor), abatacept (CD80/86 inhibitor) and ABT-122 (anti-TNF/IL-17A), respectively. One study compared ustekinumab (IL-12/23i) with TNF inhibitor therapy in patients with entheseal disease. Three articles investigated DMARD tapering. Trials on targeted synthetic DMARDs investigated apremilast (phosphodiesterase-4 inhibitor) and Janus kinase inhibitors (JAKi; tofacitinib, filgotinib). Biosimilar comparison with bio-originator showed non-inferiority. Safety was evaluated in 13 LTEs, 9 cohort studies and 1 case-control study investigating malignancies, infections, infusion reactions, multiple sclerosis and major cardiovascular events, as well as efficacy and safety of vaccination. No new safety signals were identified; however, warnings on the risk of venous thromboembolic events including pulmonary embolism when using JAKi were issued by regulators based on other studies.
    CONCLUSION: Many drugs in PsA are available and have demonstrated efficacy against placebo. Efficacy varies across PsA manifestations. Safety must also be taken into account. This review informed the development of the European League Against Rheumatism 2019 updated PsA management recommendations.
    Keywords:  DMARDs (biologic); DMARDs (synthetic); anti-TNF; psoriatic arthritis
  18. Oncol Lett. 2020 Jun;19(6): 3827-3838
    Shang K, Wang Z, Hu Y, Huang Y, Yuan K, Yu Y.
      Indoleamine 2,3-dioxygenase 1 (IDO1), which degrades the essential amino acid tryptophan, exerts immunosuppressive functions and serves a crucial role in multiple types tumor progression, including non-small-cell lung cancer (NSCLC) and melanoma. Recent studies have reported that T-cell exhaustion is increased during tumor progression, which impairs the antitumor immune response. However, the association between IDO1 and T-cell exhaustion during tumor progression remains unknown. The present study evaluated the effect of IDO1 on T-cell exhaustion in lung cancer mice. The present study demonstrated that IDO1 knockdown by small interfering RNA in the LLC cell line inhibited T-cell exhaustion. Furthermore, the role of IDO1 in T-cell exhaustion during lung cancer progression was determined in an in vivo mouse model using IDO1 short hairpin RNA (shRNA). The results demonstrated that inhibition of IDO1 activity by shRNA administration in vivo significantly delayed the onset and growth of tumors. In addition, the expression levels of the inhibitory receptors programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA) were increased in T-cells from the lung tumor-bearing mice, whereas interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) levels in serum were decreased compared with the control mice. However, no difference in the absolute number of T cells was observed, including CD4+ and CD8+ T cells. In addition, IDO1 knockdown by shRNA inhibited T-cell exhaustion in lung tumor-bearing mice, which was characterized by decreased expression of PD-1 and BTLA on T cells. By contrast, IL-2 and TNF-α levels in serum were increased in IDO1-shRNA-treated mice. By using a shRNA approach, the present study demonstrated that IDO1 activity may be involved in tumor growth, and that IDO1 silencing may inhibit tumor progression by impeding the process of T-cell exhaustion.
    Keywords:  T-cell exhaustion; immunotherapy; indoleamine 2,3 dioxygenase 1; lung cancer
  19. Biochem Soc Trans. 2020 May 07. pii: BST20191092. [Epub ahead of print]
    Sun C, Fang Y, Labrie M, Li X, Mills GB.
      Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated activity across a broad spectrum of molecular backgrounds and tumor types, with the greatest activity observed in patients with aberrations in the homologous recombination DNA damage repair pathway. Despite remarkable responses in a subset of patients, the response is usually modest and transient due to the almost inevitable emergence of resistance. Tumors develop resistance through rapid adaptation to the effects of PARPi as well as by generation or selection of genomic aberration. Although adaptive responses results in drug resistance, it also induces therapeutic vulnerabilities that could be exploited with rational combination therapies. To fulfill this role, we established the combinatorial adaptive response therapy (CART) platform by performing reverse-phase protein arrays to characterize adaptive responses, and develop rational combination therapies. Our series of studies strongly support the efficacy of this strategy, wherein targeting the emerging adaptive responses to PARPi with MEK/ERK inhibitors, WEE1/ATR inhibition (inhibitors of S-phase and G2 DNA damage checkpoint), and PI3K/AKT/mTOR inhibition, and showed promising anti-tumor activity in various preclinical models. Importantly, this approach has been proven highly efficient, and several combinational therapies developed from the CART platform are being evaluated in ongoing clinical trials (NCT03801369, NCT03586661, NCT03162627, NCT03544125, NCT02659241, NCT02208375, NCT02316834, and NCT03637491).
    Keywords:  PARP inhibitor; RPPA; adaptive response; combination therapy
  20. ACS Synth Biol. 2020 May 05.
    Gonzalez-Flo E, Alaball Pujol ME, Macia J.
      Many studies have been devoted to the engineering of cellular biosensors by exploiting intrinsic natural sensors. However, biosensors rely not only on input detection but also on an adequate response range. It is therefore often necessary to tune natural systems to meet the demands of specific applications in a predictable manner. In this study, we explored the customizability of two-component bacterial biosensors by modulating the main biosensor component, i.e. the receptor protein. We developed a mathematical model that describes the functional relationship between receptor abundance and activation threshold, sensitivity, dynamic range and operating range. The defined mathematical framework allows the design of the genetic architecture of a two-component biosensor that can perform as required with minimal genetic engineering. To experimentally validate the model and its predictions, a library of biosensors was constructed. The good agreement between theoretical designs and experimental results indicates that modulation of receptor protein abundance allows optimization of biosensor designs with minimal genetic engineering.
  21. PLoS One. 2020 ;15(5): e0232612
    Lokau J, Kleinegger F, Garbers Y, Waetzig GH, Grötzinger J, Rose-John S, Haybaeck J, Garbers C.
      Tocilizumab is a humanized monoclonal antibody that is approved for the treatment of different human inflammatory diseases, including rheumatoid arthritis and cytokine release syndrome. Tocilizumab binds to the interleukin-6 receptor (IL-6R) and thereby blocks signaling of the pro-inflammatory cytokine IL-6. Initial studies and all authority assessment reports state that tocilizumab is effective in humans, but cannot bind to the murine or rat IL-6R and thus not block IL-6 signaling in the mouse. However, several recent studies described the use of tocilizumab in mice and reported biological effects that were attributed to IL-6 blockade. In this study, we investigate the capability of tocilizumab to block IL-6 signaling using different human and murine cell lines. Our results unequivocally confirm the original state of the art that tocilizumab blocks signaling via the human IL-6R, but does not block IL-6 signaling in murine cells.
  22. Cells. 2020 Apr 30. pii: E1110. [Epub ahead of print]9(5):
    Duda P, Akula SM, Abrams SL, Steelman LS, Martelli AM, Cocco L, Ratti S, Candido S, Libra M, Montalto G, Cervello M, Gizak A, Rakus D, McCubrey JA.
      Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.
    Keywords:  GSK-3; drug resistance; natural products; targeted therapy
  23. Adv Exp Med Biol. 2020 ;1241 47-57
    Kutuzov MM, Belousova EA, Ilina ES, Lavrik OI.
      DNA is constantly attacked by different damaging agents; therefore, it requires frequent repair. On the one hand, the base excision repair (BER) system is responsible for the repair of the most frequent DNA lesions. On the other hand, the formation of poly(ADP-ribose) is one of the main DNA damage response reactions that is catalysed by members of the PARP family. PARP1, which belongs to the PARP family and performs approximately 90% of PAR synthesis in cells, could be considered a main regulator of the BER process. Most of the experimental data concerning BER investigation have been obtained using naked DNA. However, in the context of the eukaryotic cell, DNA is compacted in the nucleus, and the lowest compaction level is represented by the nucleosome. Thus, the organization of DNA into the nucleosome impacts the DNA-protein interactions that are involved in BER processes. Poly(ADP-ribosyl)ation (PARylation) is thought to regulate the initiation of the BER process at the chromatin level. In this review, we focus on the mechanisms involved in BER in the nucleosomal context and the potential effect of PARylation, which is catalysed by DNA-dependent PARP1, PARP2 and PARP3 proteins, on this process.
    Keywords:  Base excision repair; DNA damge response; NCP; Nucleosome core particle; PARP1; PARP2; PARP3; Poly(ADP-ribosyl)ation
  24. Biochim Biophys Acta Gene Regul Mech. 2020 May 03. pii: S1874-9399(19)30315-3. [Epub ahead of print] 194564
    Rice S, Roy A.
      Advances in treatment of childhood leukaemia has led to vastly improved survival rates, however some subtypes such as those characterised by MLL gene rearrangement (MLL-r), especially in infants, continue to have high relapse rates and poor survival. Natural history and molecular studies indicate that infant acute lymphoblastic leukaemia (ALL) originates in utero, is distinct from childhood ALL, and most cases are caused by MLL-r resulting in an oncogenic MLL fusion protein. Unlike childhood ALL, only a very small number of additional mutations are present in infant ALL, indicating that MLL-r alone may be sufficient to give rise to this rapid onset, aggressive leukaemia in an appropriate fetal cell context. Despite modifications in treatment approaches, the outcome of MLL-r infant ALL has remained dismal and a clear understanding of the underlying biology of the disease is required in order to develop appropriate disease models and more effective therapeutic strategies.
  25. Onco Targets Ther. 2020 ;13 3303-3318
    Guo F, Yuan Y.
      Tumor necrosis factor (TNF) is the first cytokine used in tumor biotherapy, but TNF-related drugs are limited by the lack of specific targets. Tumor necrosis factor alpha-induced proteins (TNFAIPs), derived from TNF, is a protein family and participates in proliferation, invasion and metastasis of tumor cells. In order to better understand biological functions and potential roles of TNFAIPs in malignant tumors, this paper in the form of "Gene-Protein-Tumor correlation" summarizes the biological characteristics, physiological functions and mechanisms of TNFAIPs by searching National Center of Biotechnology Information, GeneCards, UniProt and STRING databases. The relationship between TNFAIPs and malignant tumors is analyzed, and protein-protein interaction diagram in members of TNFAIPs is drawn based on TNF for the first time. We find that TNF as a key factor is related to TNFAIP1, TNFAIP3, TNFAIP5, TNFAIP6, TNFAIP8 and TNFAIP9, which can be directly involved in activating TNFAIP1, TNFAIP5, TNFAIP8 and TNFAIP9. We confirm that the mechanism of TNFAIP1, TNFAIP2 and TNFAIP3 inducing tumors may be related to NF-κB signaling pathway, but the mechanism of tumor induction by other members of TNFAIPs is not clear. In the future, translational studies are needed to explore the mechanisms of TNF-TNFAIPs-tumors.
    Keywords:  biological characteristics; malignant tumor; physiological functions; tumor necrosis factor alpha-induced proteins
  26. Trends Mol Med. 2020 May;pii: S1471-4914(20)30030-7. [Epub ahead of print]26(5): 508-518
    Chen A, Koehler AN.
      Transcription factors have roles at focal points in signaling pathways, controlling many normal cellular processes, such as cell growth and proliferation, metabolism, apoptosis, immune responses, and differentiation. Their activity is frequently deregulated in disease and targeting this class of proteins is a major focus of interest. However, the structural disorder and lack of binding pockets have made design of small molecules for transcription factors challenging. Here, we review some of the most recent developments for small molecule inhibitors of transcription factors emphasized in James Darnell's vision 17 years ago. We also discuss the progress so far on transcription factors recently nominated by genome-scale loss-of-function screens from the cancer dependency map project.
    Keywords:  Myb; Myc; NF-κB; STAT; chemical probe; transcription factor
  27. Cell. 2020 Apr 30. pii: S0092-8674(20)30388-3. [Epub ahead of print]181(3): 517-519
    Hoogenraad CC, Riol-Blanco L.
      Some children with autism spectrum disorder (ASD) show behavioral improvements when experiencing inflammation accompanied by fever; however, little is known about the mechanisms that underlie these beneficial effects. In a recent issue of Nature, Reed and colleagues demonstrate that the production of interleukin-17 (IL-17) during inflammation promotes social behavior in mouse models of neurodevelopmental disorders.
  28. Cell. 2020 Apr 30. pii: S0092-8674(20)30336-6. [Epub ahead of print]181(3): 748-748.e1
    Holland LKK, Nielsen IØ, Maeda K, Jäättelä M.
      In addition to their well-defined recycling function, lysosomes act as metabolic signaling hubs that adjust cellular metabolism according to the availability of nutrients and growth factors by regulating metabolic kinases and transcription factors on their surface. Moreover, lysosomal hydrolases and ions released to cytosol or extracellular space have recently emerged as important regulators of various cellular processes from cell death to cell division. To view this SnapShot, open or download the PDF.
  29. Nature. 2019 May 08.
    Keywords:  Careers; Lab life