bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒08‒16
eighteen papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research

  1. Semin Cell Dev Biol. 2020 Aug 05. pii: S1084-9521(19)30233-2. [Epub ahead of print]
    Speir M, Lawlor KE.
      Autoinflammatory syndromes comprise a spectrum of clinical disorders characterised by recurrent, inflammatory episodes, many of which result from the release of the pro-inflammatory cytokine, interleukin-1β (IL-1β). Inflammation and programmed cell death are tightly linked, and lytic forms of cell death, such as necroptosis and pyroptosis, are considered to be inflammatory due to the release of damage-associated molecular patterns (DAMPs). In contrast, apoptosis is traditionally regarded as immunologically silent. Recent studies, however, have uncovered a high degree of crosstalk between cell death and inflammatory signalling pathways, and effectively consolidated them into one interconnected network that converges on NLRP3 inflammasome-mediated activation of IL-1β. The receptor-interacting protein kinases (RIPK) 1 and 3 are central to this network, as highlighted by the fact that mutations in genes encoding repressors of RIPK1 and/or RIPK3 activity can lead to heightened inflammation, particularly via NLRP3 inflammasome activation. In this review, we give an overview of extrinsic cell death and inflammatory signalling pathways, and then highlight the growing number of autoinflammatory diseases that are associated with aberrant cell death and inflammasome activation.
    Keywords:  Autoinflammation; Cell death; Interleukin-1; NLRP3 inflammasome; RIP kinases; Tumour necrosis factor
  2. Cell Chem Biol. 2020 Aug 07. pii: S2451-9456(20)30293-2. [Epub ahead of print]
    Nalawansha DA, Crews CM.
      Targeted protein degradation (TPD) has emerged as an exciting new era in chemical biology and drug discovery. PROteolysis TArgeting Chimera (PROTAC) technology targets cellular proteins for degradation by co-opting the ubiquitin-proteasome system. Over the last 5 years, numerous studies have expanded our understanding of the unique mode of action and advantages of PROTACs, which has in turn spurred interest in both academia and industry to explore PROTACs as a novel therapeutic strategy. In this review, we first highlight the key advantages of PROTACs and then discuss the spatiotemporal regulation of protein degradation. Next, we explore current chemically tractable E3 ligases focusing on expanding the existing repertoire with novel E3 ligases to uncover the full potential of TPD. Collectively, these studies are guiding the development of the PROTAC technology as it emerges as a new modality in precision medicine.
    Keywords:  E3 ligase; PROTACs; PhotoPROTACs; covalent ligands; proteasome; targeted protein degradation
  3. J Leukoc Biol. 2020 Aug 10.
    Dib PRB, Quirino-Teixeira AC, Merij LB, Pinheiro MBM, Rozini SV, Andrade FB, Hottz ED.
      Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod-like receptor, and C-type lectin receptor families, plays major roles in sensing and responding to pathogen-associated or damage-associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet-mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte-mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet-induced release of neutrophil extracellular traps, platelet Ag presentation to T-cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer.
    Keywords:  innate immunity; pattern recognition receptors; platelet activation; thromboinflammation
  4. J Enzyme Inhib Med Chem. 2020 Dec;35(1): 1606-1615
    Zhang Z, Chang X, Zhang C, Zeng S, Liang M, Ma Z, Wang Z, Huang W, Shen Z.
      Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
    Keywords:  PARP-1; PROTAC; target protein knockdown
  5. Oncol Lett. 2020 Oct;20(4): 22
    Wang M, Dai W, Ke Z, Li Y.
      To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.
    Keywords:  E3 ligases; gastric cancer; signaling pathways; targeted therapy; ubiquitin
  6. J Immunol. 2020 Aug 12. pii: ji2000334. [Epub ahead of print]
    Yang CY, Chuang HC, Tsai CY, Xiao YZ, Yang JY, Huang RH, Shih YC, Tan TH.
      Dual-specificity phosphatase 11 (DUSP11, also named as PIR1) is a member of the atypical DUSP protein tyrosine phosphatase family. DUSP11 is only known to be an RNA phosphatase that regulates noncoding RNA stability. To date, the role of DUSP11 in immune cell signaling and immune responses remains unknown. In this study, we generated and characterized the immune cell functions of DUSP11-deficient mice. We identified TGF-β-activated kinase 1 (TAK1) as a DUSP11-targeted protein. DUSP11 interacted directly with TAK1, and the DUSP11-TAK1 interaction was enhanced by LPS stimulation in bone marrow-derived macrophages. DUSP11 deficiency enhanced the LPS-induced TAK1 phosphorylation and cytokine production in bone marrow-derived macrophages. Furthermore, DUSP11-deficient mice were more susceptible to LPS-induced endotoxic shock. The LPS-induced serum levels of IL-1β, TNF-α, and IL-6 were significantly elevated in DUSP11-deficient mice compared with those of wild-type mice. The data indicate that DUSP11 inhibits LPS-induced macrophage activation by targeting TAK1.
  7. Curr Med Chem. 2020 Aug 10.
    Brackett CM, Blagg BSJ.
      SUMOylation has emerged as an important post-translational modification that involves the covalent attachment of the Small Ubiquitin-like Modifier (SUMO) polypeptide to a lysine residue of a target protein. The enzymatic pathway of SUMOylation is very similar to ubiquitinylation and involves an activating enzyme, a conjugating enzyme, ligases and deconjugating enzymes. SUMOylation modulates the function of a number of proteins associated with various pathways, and in fact, dysregulation of the SUMOylation pathway is observed in both cancer and neurological diseases. In many cancers, the SUMO enzymes are upregulated and SUMO levels correlate directly with prognosis and disease progression. As a result, there has been an emphasis on the discovery and development of inhibitors of SUMOylation. In this review, the latest advances in SUMOylation inhibitors is described alongside the methods used to discover small molecule SUMOylation inhibitors, which include natural products, peptidomimetics, as well as synthetic derivatives identified via virtual screens.
    Keywords:  SUMO; cancer; enzyme inhibitors; natural products; post-translational modifications; small-molecules; ubiquitin-like
  8. Structure. 2020 Aug 05. pii: S0969-2126(20)30244-6. [Epub ahead of print]
    Chen X, Dorris Z, Shi D, Huang RK, Khant H, Fox T, de Val N, Williams D, Zhang P, Walters KJ.
      The 26S proteasome is specialized for regulated protein degradation and formed by a dynamic regulatory particle (RP) that caps a hollow cylindrical core particle (CP) where substrates are proteolyzed. Its diverse substrates unify as proteasome targets by ubiquitination. We used cryogenic electron microscopy (cryo-EM) to study how human 26S proteasome interacts with M1-linked hexaubiquitin (M1-Ub6) unanchored to a substrate and E3 ubiquitin ligase E6AP/UBE3A. Proteasome structures are available with model substrates extending through the RP ATPase ring and substrate-conjugated K63-linked ubiquitin chains present at inhibited deubiquitinating enzyme hRpn11 and the nearby ATPase hRpt4/hRpt5 coiled coil. In this study, we find M1-Ub6 at the hRpn11 site despite the absence of conjugated substrate, indicating that ubiquitin binding at this location does not require substrate interaction with the RP. Moreover, unanchored M1-Ub6 binds to this hRpn11 site of the proteasome with the CP gating residues in both the closed and opened conformational states.
    Keywords:  E6AP; Rpn11; UBE3A; cryo-EM; deubiquitinating enzyme; linear ubiquitin chains; proteasome; protein degradation; ubiquitin
  9. Cell Death Dis. 2020 Aug 14. 11(8): 628
    Johnson DC, Okondo MC, Orth EL, Rao SD, Huang HC, Ball DP, Bachovchin DA.
      Canonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4+ and CD8+ T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals.
  10. Oncol Lett. 2020 Sep;20(3): 2579-2586
    Zeng C, Xiong D, Zhang K, Yao J.
      Shank-associated RH domain interactor (SHARPIN) is a component of the linear ubiquitin chain activation complex, which is essential for p53 signaling and inflammation. Previous studies have demonstrated that SHARPIN functions in tumor cell survival, growth, invasion and tumorigenesis. These functions include the regulation of p53 proteins via poly-ubiquitination, interaction with a type II protein arginine methyltransferase 5 in melanoma cells, modulating ras-associated protein-1 through p38 and c-Jun N-terminal kinases/c-Jun signaling, and mediating phosphoinositide 3-kinase/AKT signaling via phosphatase and tensin homologue deleted on chromosome 10. Hence, SHARPIN not only participates in the inflammatory response but also serves a critical role in tumor cells. The present review summarizes the biological functions of the absence or presence of SHARPIN with regard to activating the canonical NF-κB signaling pathway and the effects on p53 and other signaling pathways for the modulation of tumorigenesis. Therefore, this review provides insight into the underlying role and mechanisms of SHARPIN in tumorigenesis, as well as its potential application in cancer therapy.
    Keywords:  LUBAC; PRMT5; PTEN; SHARPIN; p53; tumorigenesis
  11. FEBS J. 2020 Aug 12.
    Suskiewicz MJ, Palazzo L, Hughes R, Ahel I.
      Despite decades of research on ADP-ribosyltransferases (ARTs) from the poly(ADP-ribose) polymerase (PARP) family, one key aspect of these enzymes-their substrate specificity-has remained unclear. Here we briefly discuss the history of this area and, more extensively, the recent breakthroughs, including the identification of protein serine residues as a major substrate of PARP1 and PARP2 in human cells and of cysteine and tyrosine as potential targets of specific PARPs. On the molecular level, the modification of serine residues requires a composite active site formed by PARP1 or PARP2 together with a specificity-determining factor, HPF1; this represents a new paradigm not only for PARPs but generally for post-translational modification (PTM) catalysis. Additionally, we discuss the identification of DNA as a substrate of PARP1, PARP2, PARP3, and some bacterial ARTs and the discovery of non-canonical RNA capping by several PARP family members. Together, these recent findings shed new light on PARP-mediated catalysis and caution to "expect the unexpected" when it comes to further potential substrates.
    Keywords:  ADP-ribosylation; DNA repair; HPF1; PARP; PARP1; PARP9; enzymatic catalysis; poly(ADP-ribosylation); post-translational modification; specificity
  12. Ann Rheum Dis. 2020 Aug 12. pii: annrheumdis-2019-216068. [Epub ahead of print]
    Kruglov A, Drutskaya M, Schlienz D, Gorshkova E, Kurz K, Morawietz L, Nedospasov S.
      OBJECTIVES: Neutralisation of tumour necrosis factor (TNF) is widely used as a therapy for rheumatoid arthritis (RA). However, this therapy is only effective in less than a half of patients and is associated with several side effects. We hypothesised that TNF may possess non-redundant protective and immunomodulatory functions in vivo that cannot be blocked without a cost. The present work aimed to identify cellular sources of protective and pathogenic TNF, and its molecular forms during autoimmune arthritis.METHODS: Mice lacking TNF expression by distinct cell types, such as myeloid cells and T or B lymphocytes, were subjected to collagen-induced arthritis (CIA) and collagen antibody-induced arthritis. Mice lacking soluble TNF production were also employed. The severity and incidence of the disease, as well as humoral and cellular responses were assessed.
    RESULTS: Myeloid cell-derived TNF contributes to both induction and pathogenesis of autoimmune arthritis. Conversely, T cell-derived TNF is protective during the induction phase of arthritis via limiting of interleukin-12 production by dendritic cells and by subsequent control of autoreactive memory T cell development, but is dispensable during the effector phase of arthritis. B cell-derived TNF mediates severity of CIA via control of pathogenic autoantibody production.
    CONCLUSIONS: Distinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell types may be superior to pan-anti-TNF therapy.
    Keywords:  T cells; arthritis; autoimmunity; inflammation; tumor necrosis factors
  13. J Allergy Clin Immunol. 2020 Aug 06. pii: S0091-6749(20)31102-7. [Epub ahead of print]
    Kracht M, Müller-Ladner U, Schmitz ML.
      The NF-κB signaling system, a key regulator of immunological processes, also affects a plethora of metabolic changes associated with inflammation and the immune response. NF-κB-regulating signaling cascades, in concert with NF-κB-mediated transcriptional events control the metabolism at several levels. NF-κB modulates apical components of metabolic processes including metabolic hormones such as insulin and glucagon, the cellular master switches AMPK and mTOR and also numerous metabolic enzymes and their respective regulators. Vice versa, metabolic enzymes and their products also exert multi-level control of NF-κB activity, thereby creating a highly connected regulatory network. These insights have resulted in the identification of the noncanonical IKK kinases IKKɛ and TBK1, which are upregulated by overnutrition, and may therefore be suitable potential therapeutic targets for metabolic syndromes. An inhibitor interfering with the activity of both kinases reduces obesity-related metabolic dysfunctions in mouse models and the encouraging results from a recent clinical trial indicate that targeting these NF-κB pathway components improves glucose homeostasis in a subset of patients with type 2 diabetes.
    Keywords:  NF-κB; cancer; inflammation; metabolism
  14. FEBS J. 2020 Aug 11.
    Muyldermans S.
      A Nanobody (Nb) is a registered trademark of Ablynx, referring to the single antigen-binding domain of heavy chain-only antibodies (HCAbs) that are circulating in Camelidae. Nbs are produced recombinantly in micro-organisms and employed as research tools or for diagnostic and therapeutic applications. They were - and still are - also named single domain antibodies (sdAbs) or variable domain of the heavy chain of HCAbs (VHH). A variety of methods are currently in use for the fast and efficient generation of target specific Nbs. Such Nbs are produced at low cost, and associate with high affinity to their cognate antigen. They are robust, strictly monomeric and easy to tailor into more complex entities to meet the requirements of their application. Here, we review the various sources and different strategies that have been developed to identify rapidly, target-specific Nbs. We further discuss a variety of engineering technologies that have been explored to broaden the application range of Nbs and summarize those applications where designed Nbs might offer a marked advantage over other affinity reagents.
    Keywords:  Immune libraries; Nanobodies; Naïve libraries; Single domain antibodies; Synthetic libraries
  15. Nucleic Acids Res. 2020 Aug 14. pii: gkaa673. [Epub ahead of print]
    Iwasaki RS, Batey RT.
      Recent efforts in biological engineering have made detection of nucleic acids in samples more rapid, inexpensive and sensitive using CRISPR-based approaches. We expand one of these Cas13a-based methods to detect small molecules in a one-batch assay. Using SHERLOCK-based profiling of in vitrotranscription (SPRINT), in vitro transcribed RNA sequence-specifically triggers the RNase activity of Cas13a. This event activates its non-specific RNase activity, which enables cleavage of an RNA oligonucleotide labeled with a quencher/fluorophore pair and thereby de-quenches the fluorophore. This fluorogenic output can be measured to assess transcriptional output. The use of riboswitches or proteins to regulate transcription via specific effector molecules is leveraged as a coupled assay that transforms effector concentration into fluorescence intensity. In this way, we quantified eight different compounds, including cofactors, nucleotides, metabolites of amino acids, tetracycline and monatomic ions in samples. In this manner, hundreds of reactions can be easily quantified in a few hours. This increased throughput also enables detailed characterization of transcriptional regulators, synthetic compounds that inhibit transcription, or other coupled enzymatic reactions. These SPRINT reactions are easily adaptable to portable formats and could therefore be used for the detection of analytes in the field or at point-of-care situations.