bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒08‒09
eight papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research


  1. Cancers (Basel). 2020 Aug 05. pii: E2188. [Epub ahead of print]12(8):
    Shah A, Plaza-Sirvent C, Weinert S, Buchbinder JH, Lavrik IN, Mertens PR, Schmitz I, Lindquist JA.
      Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-κB activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-κB activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development.
    Keywords:  TNF; apoptosis; cold shock proteins
    DOI:  https://doi.org/10.3390/cancers12082188
  2. Front Immunol. 2020 ;11 1424
    Metcalfe RD, Putoczki TL, Griffin MDW.
      Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.
    Keywords:  IL-11; IL-6; JAK; STAT; cytokine; drug development; interleukin; structural biology
    DOI:  https://doi.org/10.3389/fimmu.2020.01424
  3. Nat Chem Biol. 2020 Aug 03.
    Mayor-Ruiz C, Bauer S, Brand M, Kozicka Z, Siklos M, Imrichova H, Kaltheuner IH, Hahn E, Seiler K, Koren A, Petzold G, Fellner M, Bock C, Müller AC, Zuber J, Geyer M, Thomä NH, Kubicek S, Winter GE.
      Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.
    DOI:  https://doi.org/10.1038/s41589-020-0594-x
  4. Neurobiol Learn Mem. 2020 Jul 31. pii: S1074-7427(20)30130-1. [Epub ahead of print] 107286
    Musaus M, Navabpour S, Jarome TJ.
      Over the last 20 years, a number of studies have provided strong support for protein degradation mediated by the ubiquitin-proteasome system in synaptic plasticity and memory formation. In this system, target substrates become covalently modified by the small protein ubiquitin through a series of enzymatic reactions involving hundreds of different ligases. While some substrates will acquire only a single ubiquitin, most will be marked by multiple ubiquitin modifications, which link together at specific lysine sites or the N-terminal methionine on the previous ubiquitin to form a polyubiquitin chain. There are at least eight known linkage-specific polyubiquitin chains a target protein can acquire, many of which are independent of the proteasome, and these chains can be homogenous, mixed, or branched in nature, all of which result in different functional outcomes and fates for the target substrate. However, as the focus has remained on protein degradation, much remains unknown about the role of these diverse ubiquitin chains in the brain, particularly during activity- and learning-dependent synaptic plasticity. Here, we review the different types and functions of ubiquitin chains and summarize evidence suggesting a role for these diverse ubiquitin modifications in synaptic plasticity and memory formation. We conclude by discussing how technological limitations have limited our ability to identify and elucidate the role of different ubiquitin chains in the brain and speculate on the future directions and implications of understanding linkage-specific ubiquitin modifications in activity- and learning-dependent synaptic plasticity.
    Keywords:  Ubiquitin; memory; protein degradation; transcription
    DOI:  https://doi.org/10.1016/j.nlm.2020.107286
  5. Front Cell Dev Biol. 2020 ;8 641
    Xue J, Hu S, Huang Y, Zhang Q, Yi X, Pan X, Li S.
      Death receptor signaling is critical for cell death, inflammation, and immune homeostasis. Hijacking death receptors and their corresponding adaptors through type III secretion system (T3SS) effectors has been evolved to be a bacterial evasion strategy. NleB from enteropathogenic Escherichia coli (EPEC) and SseK1/2/3 from Salmonella enterica serovar Typhimurium (S. Typhimurium) can modify some death domain (DD) proteins through arginine-GlcNAcylation. Here, we performed a substrate screen on 12 host DD proteins with conserved arginine during EPEC and Salmonella infection. NleB from EPEC hijacked death receptor signaling through tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD), FAS-associated death domain protein (FADD), and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas SseK1 and SseK3 disturbed TNF signaling through the modification of TRADD Arg235/Arg245 and TNFR1 Arg376, respectively. Furthermore, mouse infection studies showed that SseK1 but not SseK3 rescued the bacterial colonization deficiency contributed by the deletion of NleBc (Citrobacter NleB), indicating that TRADD was the in vivo substrate. The result provides an insight into the mechanism by which attaching and effacing (A/E) pathogen manipulate TRADD-mediated signaling and evade host immune defense through T3SS effectors.
    Keywords:  NleB; SseK; T3SS effectors; TRADD; arginine GlcNAc transferase; enteropathogenic Escherichia coli
    DOI:  https://doi.org/10.3389/fcell.2020.00641
  6. Cell. 2020 Aug 06. pii: S0092-8674(20)30869-2. [Epub ahead of print]182(3): 539-541
    Pascalau R, Kuruvilla R.
      In the skin, sympathetic nerves, arrector pili muscles, and hair follicles form a tri-lineage unit to cause piloerection or goosebumps. In this issue of Cell, Schwartz et al. report that, beyond goosebumps, muscle-anchored nerves form "synapse-like" connections with hair follicle stem cells to promote hair regeneration in response to cold.
    DOI:  https://doi.org/10.1016/j.cell.2020.07.004
  7. Cancers (Basel). 2020 Jul 29. pii: E2106. [Epub ahead of print]12(8):
    Boni J, Rubio-Perez C, López-Bigas N, Fillat C, de la Luna S.
      DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.
    Keywords:  DYRK kinases; cell cycle; cell survival; cellular signaling; expression dysregulation; kinase inhibitors; tumor progression
    DOI:  https://doi.org/10.3390/cancers12082106
  8. RNA Biol. 2020 Aug 05. 1-6
    Fischer M, Weinberger T, Schulz C.
      RNA-binding proteins regulate RNA fate and govern post-transcriptional gene regulation. A new family of RNA-binding proteins is represented by regulatory RNases (Regnase, also known as Zc3h12 or MCPIP), which have emerged as important players in immune homoeostasis. Four members, Regnase1-4, have been identified to date. Here we summarize recent findings on the role of Regnase in the regulation of RNA biology and its consequences for cell functions and inflammatory processes.
    Keywords:  RNA-binding protein; Regnase; immune cells; immune homoeostasis; inflammation
    DOI:  https://doi.org/10.1080/15476286.2020.1795584