bims-tunefa Biomed News
on Tumor necrosis factor superfamily and post-translational modifications
Issue of 2020‒07‒05
twenty-six papers selected by
John Silke
Walter and Eliza Hall Institute of Medical Research


  1. Semin Cell Dev Biol. 2020 Jun 29. pii: S1084-9521(19)30243-5. [Epub ahead of print]
    Liu Z, Chan FK.
      Receptor Interacting Protein Kinase 1 (RIPK1) and RIPK3 are key adaptors that play critical roles in inflammatory and cell death signaling. Work in recent years have shown that their activities are tightly regulated by ubiquitination, phosphorylation and proteolysis. In addition to these post-translational modifications, the expression and activities of these kinases can further be tuned by environmental changes in pH and oxygen content. Proper control of these regulatory processes is crucial for the RIP kinases to execute their functions in immune responses and tissue homeostasis. In this review, we discuss recent advance in our understanding of the molecular mechanisms that regulate the activities of the RIP kinases. We will also discuss how the different regulatory mechanisms contribute to the functions of RIPK1 and RIPK3 in different pathophysiological settings.
    Keywords:  Apoptosis; Caspase; Inflammation; Necroptosis; Phosphorylation; Ubiquitination
    DOI:  https://doi.org/10.1016/j.semcdb.2020.06.013
  2. Cell Immunol. 2020 Jun 13. pii: S0008-8749(20)30307-5. [Epub ahead of print]354 104147
    Mellett M.
      CARD14 is a scaffold molecule predominantly expressed in keratinocytes and genetic variants in the CARD14 gene confer an increased risk of inflammatory skin disease. Due to its association with common skin diseases psoriasis and atopic dermatitis, the biological function of CARD14 is of relevant interest to human health. CARD14 recruits BCL10 and MALT1 to form the CARD-BCL10-MALT1 complex, which modulates NF-κB and MAPK signalling pathways, yet little is known about how CARD14 is regulated or activated in the context of the innate immune response and in chronic inflammation. This review summarises the current understanding of the molecular function and regulatory mechanisms of CARD14 and highlights recent findings in human disease and murine mouse models.
    Keywords:  Atopic dermatitis; BCL10; CARD14/CARMA2; Inflammation; Keratinocytes; MALT1; NF-κB; Pityriasis rubra pilaris; Psoriasis
    DOI:  https://doi.org/10.1016/j.cellimm.2020.104147
  3. Immunol Lett. 2020 Jun 26. pii: S0165-2478(20)30348-5. [Epub ahead of print]226 7-11
    Tafesh-Edwards G, Eleftherianos I.
      As members of the mitogen-activated protein kinase (MAPK) family, the c-Jun N-terminal kinases (JNKs) regulate cell responses to a wide range of extrinsic and intrinsic insults, including irradiation, reactive oxygen species (ROS), DNA damage, heat, bacterial antigens, and inflammatory cytokines. Particularly, JNK signaling regulates and promotes many important physiological processes that influence metabolic and tissue homeostasis, cell death/survival, and cell damage repair and ultimately impacts the lifespan of an organism. This diverse functionality causes a variety of tissue-specific and context-specific cellular responses, mediated by various cross talks between JNK and other cellular signaling pathways. Thus, highlighting its significance as a determinant of stress responses, JNK loss-of-function mutations have been implicated in a multitude of pathologies, including neurodegenerative diseases, diabetes, and cancer. Because JNK functions are specified in a context-dependent manner and can greatly vary, the underlying causes for these different outcomes remain largely unresolved despite the gained knowledge of many regulatory roles of JNK signaling during the past two decades. In Drosophila melanogaster, JNK signaling is conserved and required for immune responses, as well as the development for morphogenetic processes (embryonic dorsal closure and thorax closure). Therefore, Drosophila innate immunity provides the ideal model to understand the complex mechanisms underlying JNK activation and regulation. In the following, we review studies in Drosophila that highlight several mechanisms by which JNK signaling influences immunity and homeostasis.
    Keywords:  Drosophila; Innate immunity; JNK signaling
    DOI:  https://doi.org/10.1016/j.imlet.2020.06.017
  4. Nat Immunol. 2020 Jul 03.
    Jin J, Xiao Y, Chang JH, Yu J, Hu H, Starr R, Brittain GC, Chang M, Cheng X, Sun SC.
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    DOI:  https://doi.org/10.1038/s41590-020-0748-8
  5. Mol Immunol. 2020 Jun 25. pii: S0161-5890(20)30390-4. [Epub ahead of print]124 190-197
    Naik SH.
      Understanding development of the dendritic cell (DC) subtypes continues to evolve. The origin and relationship of conventional DC type 1 (cDC1), cDC type 2 (cDC2) and plasmacytoid DCs (pDCs) to each other, and in relation to classic myeloid and lymphoid cells, has had a long and controversial history and is still not fully resolved. This review summarises the technological developments and findings that have been achieved at a clonal level, and how that has enhanced our knowledge of the process. It summarises the single cell lineage tracing technologies that have emerged, their application in in vitro and in vivo studies, in both mouse and human settings, and places the findings in a wider context of understanding haematopoiesis at a single cell or clonal level. In particular, it addresses the fate heterogeneity observed in many phenotypically defined progenitor subsets and how these findings have led to a departure from the classic ball-and-stick models of haematopoiesis to the emerging continuous model. Prior contradictions in DC development may be reconciled if they are framed within this revised model, where commitment to a lineage or cell type does not occur in an all-or-nothing process in defined progenitors but rather can occur at many stages of haematopoiesis in a dynamic process.
    Keywords:  Cellular barcoding; Clonal lineage tracing; Continuous model; Dendritic cell; Dendritic cell subsets; Haematopoiesis
    DOI:  https://doi.org/10.1016/j.molimm.2020.06.012
  6. J Dermatol Sci. 2020 Jun 11. pii: S0923-1811(20)30197-3. [Epub ahead of print]
    Jin L, Liu P, Yin M, Zhang M, Kuang Y, Zhu W.
      Skin diseases bring great psychological and physical impacts on patients, however, a considerable number of skin diseases still lack effective treatments, such as psoriasis, systemic lupus erythematosus, melanoma and so on. Receptor-interacting serine threonine kinase 1 (RIPK1) plays an important role in cell death, especially necroptosis, associated with inflammation and tumor. As many molecules modulate the ubiquitination of RIPK1, disruption of this checkpoint can lead to skin diseases, which can be ameliorated by RIPK1 inhibitors. This review will focus on the molecular mechanism of RIPK1 activation in inflammation as well as the current knowledges on the contribution of RIPK1 in skin diseases.
    Keywords:  Inflammation; Melanoma; Psoriasis; RIPK1; Skin disease; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.jdermsci.2020.06.001
  7. J Clin Invest. 2020 Jun 29. pii: 138103. [Epub ahead of print]
    Bulek K, Zhao J, Liao Y, Rana N, Corridoni D, Antanaviciute A, Chen X, Wang H, Qian W, Miller-Little WA, Swaidani S, Tang F, Willard BB, McCrae K, Kang Z, Dubyak GR, Cominelli F, Simmons A, Pizarro TT, Li X.
      Gasdermin D (GSDMD) induces pyroptosis via the pore-forming activity of its N-terminal domain, cleaved by activated caspases associated with the release of IL-1β. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1β-containing small extracellular vesicles (sEVs) from intestinal epithelial cells (IECs). In response to caspase-8 inflammasome activation, GSDMD, chaperoned by Cdc37/Hsp90, recruits the E3 ligase, NEDD4, to catalyze polyubiquitination of pro-IL-1β, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1β colocalize with the exosome markers CD63 and ALIX intracellularly, and GSDMD and NEDD4 are required for release of CD63+ sEVs containing IL-1β, GSDMD, NEDD4, and caspase-8. Importantly, increased expression of epithelial-derived GSDMD is observed both in patients with inflammatory bowel disease (IBD) and those with experimental colitis. While GSDMD-dependent release of IL-1β-containing sEVs is detected in cultured colonic explants from colitic mice, GSDMD deficiency substantially attenuates disease severity, implicating GSDMD-mediated release of IL-1β sEVs in the pathogenesis of intestinal inflammation, such as that observed in IBD.
    Keywords:  Cytokines; Gastroenterology; Inflammation; Inflammatory bowel disease; Innate immunity
    DOI:  https://doi.org/10.1172/JCI138103
  8. Trends Cell Biol. 2020 Jun 25. pii: S0962-8924(20)30102-1. [Epub ahead of print]
    Chong ZS, Wright GJ, Sharma S.
      Neighbouring cells can recognise and communicate with each other by direct binding between cell surface receptor and ligand pairs. Examples of cellular recognition events include pathogen entry into a host cell, sperm-egg fusion, and self/nonself discrimination by the immune system. Despite growing appreciation of cell surface recognition molecules as potential therapeutic targets, identifying key factors contributing to cellular recognition remains technically challenging to perform on a genome-wide scale. Recently, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) knockout or activation (CRISPR-KO/CRISPRa) screens have been applied to identify the molecular determinants of cellular recognition. In this review, we discuss how CRISPR-KO/CRISPRa screening has contributed to our understanding of cellular recognition processes, and how it can be applied to investigate these important interactions in a range of biological contexts.
    DOI:  https://doi.org/10.1016/j.tcb.2020.05.005
  9. J Crohns Colitis. 2020 Jun 30. pii: jjaa131. [Epub ahead of print]
    Zhou M, He J, Shi Y, Liu X, Luo S, Cheng C, Ge W, Qu C, Du P, Chen Y.
      BACKGROUND AND AIMS: There is evidence for a disturbed necroptosis function in many inflammatory diseases but its role in inflammatory bowel diseases (IBD) and the underlying mechanisms are unclear. Here, we studied the functional significance and molecular mechanisms of ABIN3, a ubiquitin-binding protein, in regulating the ubiquitination and activation of necroptosis in IBD.METHODS: The expression of necroptosis hallmarks and ABIN3 were assessed in inflamed samples of IBD patients, dextran sodium sulfate (DSS)-induced colitis models and azoxymethane (AOM)/DSS models in mice. ABIN3 were overexpressed and silenced to explore its function in regulating necroptosis, inflammation and intestinal barrier function. Immuoprecipitiation (IP) and co-IP assays were performed to investigate the crosstalk between ABIN3 and deubiquitinating enzyme A20, and the mechanisms of coordinating ubiquitination modification to regulate necroptosis.
    RESULTS: Excessive necroptosis is an important contributory factor towards the uncontrolled inflammation and intestinal barrier defects in IBD and experimental colitis. Blocking necroptosis by Nec-1s or GSK'872 significantly prevented cell death and alleviated DSS-induced colitis in vivo, whereas in AOM/DSS model, necroptosis inhibitors aggravated the severity of colitis-associated colon carcinogenesis (CAC). Mechanistically, ABIN3 is rapidly recruited to the TNF-RSC complex, which interacts and coordinates with deubiquitinating enzyme A20 to control the K63 deubiquitination modification and subsequent activation of the critical necroptosis kinase, RIPK3, to suppress necroptosis.
    CONCLUSIONS: ABIN3 regulates inflammatory response and intestinal barrier function by interacting with A20 and coordinating the K63 deubiquitination modification of necroptosis in IBD.
    Keywords:  A20; ABIN3; Necroptosis; RIPK3; inflammation; intestinal barrier; ubiquitination
    DOI:  https://doi.org/10.1093/ecco-jcc/jjaa131
  10. Expert Opin Drug Saf. 2020 Jul 02. 1-11
    Wang WM, Jin HZ.
      INTRODUCTION: Pustular psoriasis is a group of skin diseases characterized by neutrophil infiltration in the epidermis and formation of sterile pustules. Conventional treatments, such as retinoids and immunosuppressive drugs, have improved the clinical manifestations; however, many patients suffer from drug-related toxicity or are resistant to therapy.AREAS COVERED: In this review, the authors focus on the efficacy and safety of these biologics, including anti-IL-1β (gevokizumab and canakinumab), anti-IL-1 R (anakinra), anti-IL-36 R (BI 655130), anti-tumor necrosis factor-α (etanercept, infliximab, and adalimumab), anti-IL-12/23 (ustekinumab), anti-IL-17A (secukinumab and ixekizumab), anti-IL-17RA (brodalumab), anti-IL-2 R (basiliximab), anti-IL-6 R (tocilizumab), and anti-IL-23 (risankizumab and guselkumab), for treating pustular psoriasis.
    EXPERT OPINION: Patients with pustular psoriasis treated with biologics demonstrated positive responses. Anti-TNF-α is the most available biologics for the treatment of pustular psoriasis, and anti-IL-12/23 and anti-IL-17A might be considered as the first- or second-line therapy for moderate-to-severe and refractory pustular psoriasis. Anti-IL-17A can be used in the pustular psoriasis patients who failed to respond to anti-TNF agents and anti-IL-12/23. Therapeutic efficacy of biologics in pustular psoriasis might have no association with IL-36 RN mutation status.
    Keywords:  Biologics; IL-36RN; acrodermatitis continua of Hallopeau; pustular psoriasis
    DOI:  https://doi.org/10.1080/14740338.2020.1785427
  11. F1000Res. 2020 ;pii: F1000 Faculty Rev-612. [Epub ahead of print]9
    Hasegawa A, Abe R.
      Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.
    Keywords:  Stevens-Johnson syndrome; drug reaction; erythema multiforme; necroptosis; toxic epidermal necrolysis
    DOI:  https://doi.org/10.12688/f1000research.24748.1
  12. F1000Res. 2020 ;pii: F1000 Faculty Rev-653. [Epub ahead of print]9
    Han J, Wu J, Silke J.
      The p38 family is a highly evolutionarily conserved group of mitogen-activated protein kinases (MAPKs) that is involved in and helps co-ordinate cellular responses to nearly all stressful stimuli. This review provides a succinct summary of multiple aspects of the biology, role, and substrates of the mammalian family of p38 kinases. Since p38 activity is implicated in inflammatory and other diseases, we also discuss the clinical implications and pharmaceutical approaches to inhibit p38.
    Keywords:  MAPK; inflammation; p38; signalling
    DOI:  https://doi.org/10.12688/f1000research.22092.1
  13. Sci Immunol. 2019 May 03. pii: eaax8197. [Epub ahead of print]4(35):
    Cohen JN, Rosenblum MD.
      Keratinocytes regulate circulating CD8+ T cell memory after cutaneous infection.
    DOI:  https://doi.org/10.1126/sciimmunol.aax8197
  14. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May 25. 49(1): 100-106
    Wang Y, Lu Y.
      The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.
  15. Proc Natl Acad Sci U S A. 2020 Jul 02. pii: 201919565. [Epub ahead of print]
    Chan DTY, Jenkinson L, Haynes SW, Austin M, Diamandakis A, Burschowsky D, Seewooruthun C, Addyman A, Fiedler S, Ryman S, Whitehouse J, Slater LH, Gowans E, Shibata Y, Barnard M, Wilkinson RW, Vaughan TJ, Holt SV, Cerundolo V, Carr MD, Groves MAT.
      Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time. In this study, we used a method that combined antibody chain shuffling and a staggered-extension process to produce unbiased libraries, which recombined beneficial mutations from all six complementarity-determining regions (CDRs) in the affinity maturation of an inhibitory antibody to Arginase 2 (ARG2). We made use of the vast display capacity of ribosome display to accommodate the sequence space required for the diverse library builds. Further diversity was introduced through pool maturation to optimize seven leads of interest simultaneously. This resulted in antibodies with substantial improvements in binding properties and inhibition potency. The extensive sequence changes resulting from this approach were translated into striking structural changes for parent and affinity-matured antibodies bound to ARG2, with a large reorientation of the binding paratope facilitating increases in contact surface and shape complementarity to the antigen. The considerable gains in therapeutic properties seen from extensive sequence and structural evolution of the parent ARG2 inhibitory antibody clearly illustrate the advantages of the unbiased approach developed, which was key to the identification of high-affinity antibodies with the desired inhibitory potency and specificity.
    Keywords:  Arginase 2; affinity maturation; antibody engineering; inhibitory antibodies; ribosome display
    DOI:  https://doi.org/10.1073/pnas.1919565117
  16. J Am Acad Dermatol. 2020 Jun 25. pii: S0190-9622(20)31177-4. [Epub ahead of print]
    Giesey RL, Mehrmal S, Uppal P, Delost ME, Delost GR.
      
    Keywords:  Acne vulgaris; Basal cell carcinoma; Contact dermatitis; Disability adjusted life years (DALYs); Global Burden of Disease Study (GBD) database; Global medicine; Gross domestic product (GDP) per capita; Human immunodeficiency virus (HIV); Melanoma; Pruritus; Psoriasis; Pyoderma; Scabies; Socioeconomic status; Squamous cell carcinoma; Syphilis; Urticaria; Viral skin diseases
    DOI:  https://doi.org/10.1016/j.jaad.2020.05.157
  17. Immunol Invest. 2020 Jun 29. 1-16
    Soltani S, Mahmoudi M, Farhadi E.
      Dendritic cells (DCs) are considered as a subset of mononuclear phagocytes that composed of multiple subsets with distinct phenotypic features. DCs play crucial roles in the initiation and modulation of immune responses to both allo- and auto-antigens during pathogenic settings, encompassing infectious diseases, cancer, autoimmunity, transplantation, as well as vaccination. DCs play a role in preventing autoimmunity via inducing tolerance to self-antigens. This review focus on the most common subsets of DCs in human. Owing to the low frequencies of DC cells in blood and tissues and also the lack of specific DC markers, studies of DCs have been greatly hindered. Human DCs arise by a dedicated pathway of lympho-myeloid hematopoiesis and give rise into specialized subtypes under the influence of transcription factors that are specific for each linage. In humans, the classification of DCs has been generally separated into the blood and cutaneous subsets, mainly because these parts are more comfortable to examine in humans.
    Keywords:  Human dendritic cell subset; dendritic cell classification; immune responses; tolerogenic dendritic cell
    DOI:  https://doi.org/10.1080/08820139.2020.1783289
  18. FEBS J. 2020 Jul 03.
    Razai AS, Snipas SJ, Poreba M, Fasci D, Salvesen GS.
      Many proteases recognize their substrates with high specificities, with this in mind, it should theoretically be possible to utilize the substrate binding cleft of a protease as a scaffold to engineer an affinity reagent. In this study, we sought to develop reagents that would differentiate between substrates and products of proteolysis, based on a caspase 7 scaffold. Firstly, we engineered a form of caspase 7 that can undergo conversion to a substrate binding conformation without catalysis. Seeking to generate a product-only trap, we further engineered this construct by incorporating mutations that compensate for the generation of a negative charge in the neo C-terminus of a newly generated product. This was accomplished with only three substitutions within the substrate binding cleft. Moreover, the affinity of the product trap for peptides was comparable to the affinity of caspase 7 to parental substrates. Finally, generation of a hybrid fluorescent protein with the product trap provided a reagent that specifically recognized apoptotic cells and highlights the versatility of such an approach in developing affinity and imaging agents for a variety of cysteine and serine proteases..
    Keywords:  Protease trap; apoptosis; mutagenesis; protein engineering; proteolysis imaging
    DOI:  https://doi.org/10.1111/febs.15467
  19. Elife. 2020 Jun 29. pii: e56720. [Epub ahead of print]9
    Manils J, Webb LV, Howes A, Janzen J, Boeing S, Bowcock AM, Ley SC.
      To investigate how the CARD14E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14E138A induced more extensive skin inflammation and a severe systemic disease involving infiltration of myeloid cells in multiple organs, temperature reduction, weight loss and organ failure. This severe phenotype resembled acute exacerbations of generalized pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14E138A signalling only in keratinocytes. These results suggest that anti-inflammatory therapies specifically targeting keratinocytes, rather than systemic biologicals, might be effective for GPP treatment early in disease progression.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.56720
  20. Curr Opin Struct Biol. 2020 Jun 30. pii: S0959-440X(20)30078-6. [Epub ahead of print]65 51-60
    Ludewig H, Molyneux S, Ferrinho S, Guo K, Lynch R, Gkotsi DS, Goss RJ.
      Over 5000 halogenated natural products have been reported so far, many of these arising from the marine environment. The introduction of a halogen into a molecule can significantly impact its bioavailability and bioactivity. More recently enzymatic halogenation has been used to enable late stage functionalisation through site-selective halogenation and cross-coupling. Halogenases are becoming increasingly valued tools. This review outlines the various classes of halogenases that have been discovered, and examines these from both a structural and a mechanistic perspective, reflecting upon the many recent advances in halogenase discovery.
    DOI:  https://doi.org/10.1016/j.sbi.2020.05.012
  21. Trends Biochem Sci. 2020 Jun 25. pii: S0968-0004(20)30145-6. [Epub ahead of print]
    Cambronne XA, Kraus WL.
      The numerous biological roles of NAD+ are organized and coordinated via its compartmentalization within cells. The spatial and temporal partitioning of this intermediary metabolite is intrinsic to understanding the impact of NAD+ on cellular signaling and metabolism. We review evidence supporting the compartmentalization of steady-state NAD+ levels in cells, as well as how the modulation of NAD+ synthesis dynamically regulates signaling by controlling subcellular NAD+ concentrations. We further discuss potential benefits to the cell of compartmentalizing NAD+, and methods for measuring subcellular NAD+ levels.
    Keywords:  CD38; nicotinamide mononucleotide adenylyltransferase (NMNAT); nicotinamide phosphoribosyltransferase (NAMPT); poly(ADP-ribose) polymerase (PARP); sirtuin
    DOI:  https://doi.org/10.1016/j.tibs.2020.05.010
  22. Cell. 2020 Jun 25. pii: S0092-8674(20)30688-7. [Epub ahead of print]
    Luoma AM, Suo S, Williams HL, Sharova T, Sullivan K, Manos M, Bowling P, Hodi FS, Rahma O, Sullivan RJ, Boland GM, Nowak JA, Dougan SK, Dougan M, Yuan GC, Wucherpfennig KW.
      Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
    Keywords:  CTLA-4; IFNγ; PD-1; TNFα; Trm; cancer; checkpoint blockade; cytotoxic T cells; immune-related adverse events; inflammatory cytokines; irAEs; tissue-resident memory T cells
    DOI:  https://doi.org/10.1016/j.cell.2020.06.001
  23. Immunity. 2020 Jun 28. pii: S1074-7613(20)30272-7. [Epub ahead of print]
    Mangalmurti N, Hunter CA.
      The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in "ideal" responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.
    DOI:  https://doi.org/10.1016/j.immuni.2020.06.017
  24. Chembiochem. 2020 Jul 04.
    Li Y, Hua X, Chu G.
      Ubiquitin chains with distinct topologies play essential roles in eukaryotic cells. Recently, it was discovered that multiple ubiquitin units can be ligated to more than one lysine residue in the same ubiquitin to form diverse branched ubiquitin chains. Although there is increasing evidence implicating these branched chains in a plethora of biological functions, few mechanistic details have been elucidated. This concept article introduces the function, detection and chemical synthesis of branched ubiquitin chains; and offers some future perspective for this exciting new field.
    Keywords:  Ubiquitin probe; branched ubiquitin chains; chemical ubiquitination; protein chemical synthesis
    DOI:  https://doi.org/10.1002/cbic.202000295
  25. Cancer Discov. 2020 Jun 30. pii: CD-20-0226. [Epub ahead of print]
    Nagashima H, Lee CK, Tateishi K, Higuchi F, Subramanian M, Rafferty S, Melamed L, Miller JJ, Wakimoto H, Cahill DP.
      Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. Poly(ADP-ribose) polymerases (PARPs) catalyze oligomerization of NAD+ monomers into poly(ADP-ribose) (PAR) chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here, we find that, in endogenous IDH1 mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0226