DOCSLIB.ORG

1 SUPPORTING RESULTS Generation of the Initial STAND

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 SUPPORTING RESULTS Generation of the Initial STAND SUPPORTING RESULTS Generation of the Initial STAND Markov Model To obtain a large number of STAND NTPase domains from protein databases, we generated a hidden Markov model to serve as a probe sensitive to both NACHT and NB-ARC domains. We first selected an initial set of 207 canonical NB-ARC and NACHT domain peptide sequences, including NB-ARC domains of R-proteins, APAF1, and related fungal and bacterial NTPases as well as the NACHT domains of NOD-like receptors. The numbers of NACHT and NB-ARC sequences in this starting set were approximately equal. Starting with these 207 sequences, we used the CD-HIT program (1) to cluster the sequences by degree of sequence identity, and to pick representative sequences that reflected their overall diversity (see Methods), leaving 133, that we aligned using MUSCLE (2) and manual realignment. This alignment, which included 68 NACHT and 65 NB-ARC domain sequences, was used as the training set to generate a custom STAND hidden Markov model (HMM) using the hmmbuild program from the HMMER package (3). While this custom HMM, which we refer to as STAND-HMM, is tuned for the NB-ARC and NACHT subfamilies of the STAND NTPases, it is also sensitive to the SWACOS and MalT clades, but only weakly to the MNS clade. Mining of Genbank for NTPase Domains and Subsequent Iterative Alignments and Phylogeny The STAND Markov model, STAND-HMM was used to probe the NCBI NR protein set containing 10,565,004 sequences, thereby identifying 15,500 STAND NTPases with scores of 30 or greater, a threshold that our analysis indicated was appropriate for detecting known NACHT and NB-ARC sequences while rejecting fragmentary and spurious matches (Figure S2). The CD-HIT program (1) program was then used to select a representative subset of these sequences 1 with a 90% identity cutoff, resulting in a set of 5,679 representative NBS domains. The HMMER hmmalign program which aligns sequences using an HMM as a guide was then used to create an initial alignment of these sequences with the STAND-HMM. Because this Markov model-guided alignment was well aligned only in the most highly conserved regions of the STAND NTPases, SeaView (4) was used to align regions with less conservation using the MUSCLE (2) or MAFFT (5) options, as well as manual alignment. For ease of handling and analysis, the alignment was split into two separate subset alignments of 4,178 NB-ARC (including SWACOS, and MalT, plus 10 NACHT domain sequences from Leipe et al. as outgroups) and 1,501 NACHT domains that were handled separately before reuniting for final ML tree generation. To further simplify the process of alignment, a quarter of these domains (1,045 sequences for the NB-ARC alignment, and 377 for the NACHTS) were randomly selected. Of these, 817 NB-ARC and 286 NACHT domains had associated C-Terminal HETHS domains (~150 amino acids) in their source protein sequences. In order to benefit from the additional phylogenetic information included in these HETHS domains, the corresponding HETHS domains amino acid sequences were appended to the 817 NB-ARC + HETHS sequences and 286 NACHT + HETHS sequences, and aligned as described above. Maximum likelihood phylogenies were inferred from these remaining 817 NB-ARC and outgroup sequences and 271 NACHT sequences using RAxML, with 100 bootstraps. To identify rogue taxa, the script 'compare_trees_leaf_correlation.pl', developed in-house, was run on these sets of 100 bootstraps to calculate correlation coefficients of reciprocal distance, where distance is the number of branches between two tree leaves (Supporting Methods). Taxa with correlation coefficients of reciprocal distance less than 0.8 were excluded from further analysis, further winnowing the number of remaining sequences to 664 NB-ARC and 271 NACHT sequences (Figure S2). The minimal value of 0.8 was chosen as a threshold to 2 remove the taxa with the greatest variability in nearest neighbors while keeping the most phylogenetically stable taxa. Lastly, a set of 15 NB-ARC, 2 MalT, 2 SWACOS, and 10 NACHT NTPase domains previously identified by of Leipe and coworkers was added to the sequence alignments to serve as markers for clades identified in that earlier work (6). MalT and SWACOS, and NACHT domains served as outgroups. Also, a single TIR-NBS-WD40, identified in the Medicago truncatula genome sequencing project, which was of interest from an evolutionary standpoint, was included. The alignments were combined into a single alignment containing 964 NBS + HETHS domains. DNA sequences were highly divergent and were not used for phylogeny reconstruction. Survey of NBS, NBS-LRR, NBS-WD40, NBS-TPR and NBS-ARM Domain Structures in the NCBI NR Protein Database. The NCBI Protein NR Set from March 11, 2010 was scanned for matches to the STAND- HMM with scores of 30 or greater, as described in Supporting Methods. This cutoff was chosen to limit matches to complete STAND domains closely matching the model. Proteins with matches to the STAND-HMM were then scanned for C-terminal matches to ARM, LRR, TPR, and WD40 repeat Markov models obtained from PFAM, and associated with NCBI taxonomic information. The totals of NBS, NBS-ARM, NBS-LRR, NBS-TPR, and NBS-WD40 domain combinations in various eukaryotic clades are compiled in Table S5. In the NCBI NR Database (March 11, 2010 release), 12,549 (82%) of identified STAND NBS domains are in eukaryotic proteins, 2,685 (17.5%) in bacterial proteins, and fractions of a percent in archaeal and viral proteins. However, the vast majority (99.7% or 4,376 out of 4,388) of proteins with NBS-LRR architecture occur in eukaryotic sequences, the only exception being a small group of 12 NACHT-LRR proteins from actinobacteria and planctomycetes (Table S3). 3 In contrast, the NBS-WD40 architecture occurs within eukaryotes and prokaryotes in approximately the same proportions as the NBS domain itself. The NBS-TPR domain architecture, on the other hand, is predominantly bacterial. The NBS-ARM domain architecture is extremely rare, with only 51 identified occurrences across the NCBI NR data set, including archaea, bacterial, and metazoan clades. Among eukaryotic sequences from NCBI, the NBS- LRR architecture is restricted to plants and metazoans, except for a single protein from Tetrahymena thermophila (XP_001030846.1) that possesses an unusual combination of an NTPase plus a series of WD40 and LRR repeats. Aside from some homologs in other alveolates and in the related rhizaria, the closest homologs of the STAND NTPase of this Tetrahymena protein are eubacterial, suggesting a possible acquisition by horizontal gene transfer. Survey of NBS-LRR, NBS-WD40, and NBS-TPR Domain Combinations in Sequenced Eukaryotic Genomes Protein sequences and gene annotation data for 46 representative eukaryotic genomes representing a broad phylogenetic sampling were downloaded from their respective genome repositories (Dataset S1). These 46 full-genome sequences, which included both finished and draft genomes, were downloaded in October 2013 and therefore contain sequences not represented in the NCBI NR Database March 11, 2010 release described above. Protein data sets were scanned for the domain combinations of interest as described in Supporting Methods, and the number of each type of domain architecture in each genome identified is presented in Figure 2. In this case, a maximum E-value of 10 was required for individual matches so as to be permissive, and allow for maximal sensitivity for detection of STAND NTPases and repeat domains. Minor differences between the NCBI NR set survey and the eukaryotic genomes survey reflect the higher sensitivity of the latter survey, and the inclusion of recently-sequenced 4 and draft genomes from October 2013. The NBS-LRR domain combination appears in 25 of the 46 surveyed eukaryotic genomes. As in the NCBI database survey, there are few occurrences of NBS-LRR sequences outside of land plants and metazoa. Consistent with the NCBI database survey, among the 46 eukayotic genomes surveyed, the NBS-WD40 and NBS-TPR architectures have a fairly broad phylogenetic distribution, whereas NBS-LRRs are predominantly associated with plants and metazoans. The NBS-LRR architecture is absent from the genome of Mnemiopsis leidyi, a representative of the ctenophores (comb jellies), which have been suggested to be the earliest diverging metazoans (7), but there are ten proteins with this architecture in the sponge Amphimedon queenslandica, nine of which are clearly homologs of the NLRs of vertebrates. This suggests that NLRs might have evolved after the divergence of ctenophores and all other metazoans. NBS-LRR proteins are absent in the unicellular chlorophyte algae Ostreococcus tauri and Chlamydomonas reinhardtii, but their presence in all of the multicellular viridiplantae, including reports of a remarkable variety of R-proteins in the liverwort Marchantia polymorpha (8), suggests that proteins with the NBS-LRR architecture evolved very early in the evolution of multicellular plants. Furthermore, the observation in the multicellular alga, Klebsormidium flaccidum (9) of two proteins of the TIR-NBS-LRR domain structure (kfl00170_0010_v1.1, and kfl00295_0030_v1.1) with STAND NTPases similar to those of Clade I seemingly pushes the genesis of R-proteins back before the divergence of charophyte algae and land plants. Of the six NBS-LRR domain combination detected outside the metazoan and viridiplantae clades, most seem to be in some ways exceptional, with other domains interposed between the NBS and the LRR, or with weak or truncated NTPase or LRR hits (Supporting Table 6). It is likely that the fairly permissive criteria of this survey contributed to their detection. Upon 5 examination, most of these NBS-LRR candidates appear to be poor analogs of R-proteins or NOD-like receptors, with such architectures as LRR-NBS-LRR (Ectocarpus silicosus, Esi0031_0015), Trans-Membrane-NBS-LRR (Naegleria gruberi, jgi|Naegr1|54705|fgeneshHS_pg.scaffold_166000001), and NBS-WD40-LRR (Tetrahymena thermophila, TTHERM_01006540), with STAND-NTPases apparently unrelated to those of R- proteins or NLRs.
Load more

Recommended publications
  • Bacillus Anthracis
    The FIIND domain of Nlrp1b promotes oligomerization and pro-caspase-1 activation in response to lethal toxin of Bacillus anthracis by Vineet Joag A thesis submitted in conformity with the requirements for the degree of Masters of Science Graduate Department of Laboratory Medicine and Pathobiology University of Toronto ©Copyright by Vineet Joag (2010) The FIIND domain of Nlrp1b promotes oligomerization and pro- caspase-1 activation in response to lethal toxin of Bacillus anthracis Vineet Joag Masters of Science Laboratory Medicine and Pathobiology University of Toronto 2010 Abstract Lethal toxin (LeTx) of Bacillus anthracis kills murine macrophages in a caspase-1 and Nod-like- receptor-protein 1b (Nlrp1b)-dependent manner. Nlrp1b detects intoxication, and self-associates to form a macromolecular complex called the inflammasome, which activates the pro-caspase-1 zymogen. I heterologously reconstituted the Nlrp1b inflammasome in human fibroblasts to characterize the role of the FIIND domain of Nlrp1b in pro-caspase-1 activation. Amino-terminal truncation analysis of Nlrp1b revealed that Nlrp1b1100-1233, containing the CARD domain and amino-terminal 42 amino acids within the FIIND domain was the minimal region that self- associated and activated pro-caspase-1. Residues 1100EIKLQIK1106 within the FIIND domain were critical for self-association and pro-caspase-1 activation potential of Nlrp1b1100-1233, but not for binding to pro-caspase-1. Furthermore, residues 1100EIKLQIK1106 were critical for cell death and pro-caspase-1 activation potential of full-length Nlrp1b upon intoxication. These data suggest that after Nlrp1b senses intoxication, the FIIND domain promotes self-association of Nlrp1b, which activates pro-caspase-1 zymogen due to induced pro-caspase-1 proximity.
    [Show full text]
  • Role of NLRP3 Inflammasome Activation in Obesity-Mediated
    International Journal of Environmental Research and Public Health Review Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders Kaiser Wani , Hind AlHarthi, Amani Alghamdi , Shaun Sabico and Nasser M. Al-Daghri * Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] (K.W.); [email protected] (H.A.); [email protected] (A.A.); [email protected] (S.S.) * Correspondence: [email protected]; Tel.: +966-14675939 Abstract: NLRP3 inflammasome is one of the multimeric protein complexes of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing pyrin and HIN domain family (PYHIN). When ac- tivated, NLRP3 inflammasome triggers the release of pro-inflammatory interleukins (IL)-1β and IL-18, an essential step in innate immune response; however, defective checkpoints in inflamma- some activation may lead to autoimmune, autoinflammatory, and metabolic disorders. Among the consequences of NLRP3 inflammasome activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Understanding the mechanisms involved in the regulation of NLRP3 inflammasome in adipose tissue may help in the development of specific inhibitors for the treatment and prevention of obesity-mediated metabolic diseases. In this narrative review, the current understanding of NLRP3 inflammasome activation and regulation is highlighted, including its putative roles in adipose tissue dysfunction and insulin resistance. Specific inhibitors of NLRP3 inflammasome activation which can potentially be used to treat metabolic disorders are also discussed. Keywords: NLRP3 inflammasome; metabolic stress; insulin resistance; diabetes; obesity Citation: Wani, K.; AlHarthi, H.; Alghamdi, A.; Sabico, S.; Al-Daghri, N.M. Role of NLRP3 Inflammasome 1.
    [Show full text]
  • A Novel LRRK2 Variant P.G2294R in the WD40 Domain Identified in Familial Parkinson's Disease Affects LRRK2 Protein Levels
    International Journal of Molecular Sciences Article A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels Jun Ogata 1, Kentaro Hirao 2, Kenya Nishioka 3 , Arisa Hayashida 3, Yuanzhe Li 3, Hiroyo Yoshino 4, Soichiro Shimizu 2, Nobutaka Hattori 1,3,4 and Yuzuru Imai 1,* 1 Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; [email protected] (J.O.); [email protected] (N.H.) 2 Department of Geriatric Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; [email protected] (K.H.); [email protected] (S.S.) 3 Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; [email protected] (K.N.); [email protected] (A.H.); [email protected] (Y.L.) 4 Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-3-6801-8332 Abstract: Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkin- son’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene- Citation: Ogata, J.; Hirao, K.; panel screening in a patient with familial PD.
    [Show full text]
  • Supplementary A
    Genomic Analysis of the Immune Gene Repertoire of Amphioxus Reveals Extraordinary Innate Complexity and Diversity Supplementary A Content 1 TLR system....................................................................................................................................2 2 NLR system ...................................................................................................................................4 3 LRRIG genes .................................................................................................................................5 4 Other LRR-containing models.......................................................................................................6 5 Domain combinations in amphioxus C-type lectins ......................................................................8 References.........................................................................................................................................9 Table S1. Cross-species comparison of the immune-related protein domains................................10 Table S2. Information of 927 amphioxus CTL gene models containing single CTLD domain. ....11 Table S3. Grouping of the amphioxus DFD gene models based on their architectures..................12 Figure S1. Two structural types of TLR. ........................................................................................13 Figure S2. Phylogenetic analysis of amphioxus P-TLRs and all vertebrate TLR families.............14 Figure S3. Phylogenetic analysis of amphioxus TLRs
    [Show full text]
  • ATP-Binding and Hydrolysis in Inflammasome Activation
    molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure.
    [Show full text]
  • Blau Syndrome Polymorphisms in NOD2 Identify Nucleotide Hydrolysis and Helical Domain 1 As Signalling Regulators ⇑ Rhiannon Parkhouse A, Joseph P
    FEBS Letters 588 (2014) 3382–3389 journal homepage: www.FEBSLetters.org Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators ⇑ Rhiannon Parkhouse a, Joseph P. Boyle a,b, Tom P. Monie a,b, a Department of Biochemistry, University of Cambridge, Cambridge, UK b Department of Veterinary Medicine, University of Cambridge, Cambridge, UK article info abstract Article history: Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level Received 10 June 2014 provides a starting point for improved therapeutic intervention. SNPs in the innate immune recep- Revised 23 July 2014 tor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syn- Accepted 23 July 2014 drome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show Available online 2 August 2014 that these polymorphisms cluster into two primary locations: the ATP/Mg2+-binding site and helical Edited by Renee Tsolis domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods. Keywords: Nucleotide-binding, leucine-rich repeat Ó 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical containing receptor Societies. This is an open access article under the CC BY license (http://creativecommons.org/licenses/
    [Show full text]
  • NLRP3) Inflammasome Activity Is Regulated by and Potentially Targetable Through Bruton Tyrosine Kinase
    Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase Thesis submitted as requirement to fulfill the degree „Doctor of Philosophy“ (Ph.D.) at the Faculty of Medicine Eberhard Karls University Tübingen by Xiao Liu (刘晓) from Shandong, China 2018 1 Dean: Professor Dr. I. B. Autenrieth 1. Reviewer: Professor A. Weber 2. Reviewer: Professor S. Beer-Hammer 2 Content Content Figures ..................................................................................................................................................... iv Tables ....................................................................................................................................................... vi Abbreviations ........................................................................................................................................ vii 1 Introduction ....................................................................................................................................... 1 1.1 The human immune system .................................................................................................... 1 1.1.1 Innate immune response ................................................................................................................... 1 1.1.2 Adaptive immune response ............................................................................................................. 2 1.2 Inflammasomes are a group of
    [Show full text]
  • De Novo PHIP Predicted Deleterious Variants Are Associated with Developmental Delay, Intellectual Disability, Obesity, and Dysmorphic Features
    Downloaded from molecularcasestudies.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press De novo PHIP predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features Running title: Case study of two patients with PHIP variants Emily Webster1, Megan T. Cho2, Nora Alexander2, Sonal Desai3, Sakkubai Naidu3, Mir Reza Bekheirnia4, Andrea Lewis4, Kyle Retterer2, Jane Juusola2, Wendy K. Chung1,5 1Department of Pediatrics, Columbia University Medical Center, New York, NY, USA 2GeneDx, Gaithersburg, MD, USA 3Kennedy Krieger Institute, Baltimore, MD, USA 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 5Department of Medicine, Columbia University Medical Center, New York, NY, USA Correspondence: Wendy K. Chung, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, USA, Tel: +1 212 851 5313, Fax: +1 212 851 5306, [email protected] Running title: PHIP variants cause developmental delay and obesity 1 Downloaded from molecularcasestudies.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract Using whole exome sequencing, we have identified novel de novo heterozygous Pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1 including PHIP have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations.
    [Show full text]
  • Three Domains for an Antimicrobial Triad
    Cell Death and Differentiation (2006) 13, 798–815 & 2006 Nature Publishing Group All rights reserved 1350-9047/06 $30.00 www.nature.com/cdd Review TIR, CARD and PYRIN: three domains for an antimicrobial triad C Werts1, SE Girardin2,3,4 and DJ Philpott*,1,5 IRF, interferon-regulatory factor; LPS, lipopolysaccharide; LRR, leucine-rich repeats; MDP, muramyl dipeptide; Mur-triLys, N- 1 Innate Immunity and Signalisation, Institut Pasteur, 28, Rue du Dr. Roux, acetylmuramic acid-L-Ala-g-D-Glu-L-LYS; Mur-triDAP, N-acetyl- 75724 Paris Cedex 15, France muramic acid-L-Ala-g-D-Glu-mesoDap; MWS, Muckle–Wells 2 Unite´ de Pathoge´nie Microbienne Mole´culaire, INSERM U389, Institut Pasteur, syndrome; NACHT domain, domain present in NAIP, CIITA, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France HET-E, TP-1; NALP, NACHT-LRR-PYD-containing protein; 3 Groupe Inserm Avenir ‘Peptidoglycan and Innate Immunity,’ Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France NOD, nucleotide-binding oligomerization domain; PAMP, patho- 4 Current address: Department of Laboratory Medicine & Pathobiology, gen-associated molecular pattern; PBMCs, peripheral blood University of Toronto, Toronto, Ontario, Canada H551A8. mononuclear cells (PBMCs); PG, peptidoglycan; PRM, pattern- 5 Current address: Department of Immunology, University of Toronto, Toronto, recognition molecule; TIR domain, Toll/interleukin-1 receptor Ontario, Canada H551A8. Tel: 416 978 7527; Fax: 416 978 1938; domain; TLR, Toll-like receptor; TNF, tumor necrosis factor; E-mail: [email protected] triDAP, L-Ala-g-D-Glu-meso-diaminopimelic acid; SLE, systemic * Corresponding author: DJ Philpott, Institut Pasteur, 28 rue du Dr.
    [Show full text]
  • Bruton Tyrosine Kinase Deficiency Augments NLRP3 Inflammasome Activation and Causes IL-1Β–Mediated Colitis
    Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis Liming Mao, … , Adrian Wiestner, Warren Strober J Clin Invest. 2020;130(4):1793-1807. https://doi.org/10.1172/JCI128322. Research Article Gastroenterology Graphical abstract Find the latest version: https://jci.me/128322/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis Liming Mao,1 Atsushi Kitani,1 Eitaro Hiejima,1 Kim Montgomery-Recht,2 Wenchang Zhou,3 Ivan Fuss,1 Adrian Wiestner,4 and Warren Strober1 1Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA. 2Clinical Research Directorate/ Clinical Monitoring Research Program, Leidos Biomedical Research Inc., National Cancer Institute (NCI) Campus at Frederick, Frederick, Maryland, USA. 3Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute (NHLBI), and 4Lymphoid Malignancies Section, Hematology Branch, NHLBI, NIH, Bethesda, Maryland, USA. Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non–B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain– containing 3 (NLRP3) inflammasome. We found that bone marrow–derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib.
    [Show full text]
  • Coronin 3 Involvement in F-Actin-Dependent Processes at the Cell Cortex
    Coronin 3 involvement in F-actin-dependent processes at the cell cortex Author Rosentreter, Andre, Hofmann, Andreas, Xavier, Charles-Peter, Stumpf, Maria, Noegel, Angelika A, Clemen, Christoph S Published 2007 Journal Title Experimental Cell Research DOI https://doi.org/10.1016/j.yexcr.2006.12.015 Copyright Statement © 2007 Elsevier. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version. Downloaded from http://hdl.handle.net/10072/14982 Griffith Research Online https://research-repository.griffith.edu.au Elsevier Editorial System(tm) for Experimental Cell Research Manuscript Draft Manuscript Number: Title: Coronin 3 involvement in F-actin dependent processes at the cell cortex Article Type: Research Article Section/Category: Keywords: Coro1C; CRNN4; WD40-repeat; F-actin; cell motility; cytoskeleton; siRNA Corresponding Author: Dr. Christoph Stephan Clemen, Corresponding Author's Institution: Institute of Biochemistry I First Author: André Rosentreter Order of Authors: André Rosentreter; Andreas Hofmann; Charles-Peter Xavier; Maria Stumpf; Angelika Anna Noegel; Christoph Stephan Clemen Manuscript Region of Origin: Abstract: The actin interaction of coronin 3 has been mainly documented by in vitro experiments. Here, we discuss coronin 3 properties in the light of new structural information and focus on assays that reflect in vivo roles of coronin 3 and its impact on F-actin associated functions. Using GFP-tagged coronin 3 fusion proteins and RNAi silencing we show that coronin 3 has roles in wound healing, protrusion formation, cell proliferation, cytokinesis, endocytosis, axonal growth, and secretion.
    [Show full text]
  • Coronin7 Regulates WASP and SCAR Through CRIB Mediated Interaction
    www.nature.com/scientificreports OPEN Coronin7 regulates WASP and SCAR through CRIB mediated interaction with Rac proteins Received: 12 May 2015 1,† 1 1 1 Accepted: 28 August 2015 Karthic Swaminathan , Maria Stumpf , Rolf Müller , Anna-Carolin Horn , 1 1 2 3 Published: 28 September 2015 Julia Schmidbauer , Ludwig Eichinger , Annette Müller-Taubenberger , Jan Faix & Angelika A. Noegel1 Coronin7 (CRN7) stabilizes F-actin and is a regulator of processes associated with the actin cytoskeleton. Its loss leads to defects in phagocytosis, motility and development. It harbors a CRIB (Cdc42- and Rac-interactive binding) domain in each of its WD repeat domains which bind to Rac GTPases preferably in their GDP-loaded forms. Expression of wild type CRN7 in CRN7 deficient cells rescued these defects, whereas proteins with mutations in the CRIB motifs which were associated with altered Rac binding were effective to varying degrees. The presence of one functional CRIB was sufficient to reestablish phagocytosis, cell motility and development. Furthermore, by molecular modeling and mutational analysis we identified the contact regions between CRN7 and the GTPases. We also identified WASP, SCAR and PAKa as downstream effectors in phagocytosis, development and cell surface adhesion, respectively, since ectopic expression rescued these functions. Coronins are a large family of evolutionary conserved proteins. They consist of a WD (Tryptophane- Aspartate)-repeat domain containing seven repeats that form a seven-bladed β -propeller structur- ally resembling the Gβ subunit of the heterotrimeric G-proteins. This region is followed by a unique region and a C-terminal coiled coil region which mediates oligomerization. Coronins play roles in actin cytoskeleton-associated processes, in signal transduction, in endosomal trafficking, survival of pathogenic bacteria in macrophages and homeostatic T cell signalling1–3.
    [Show full text]