DOCSLIB.ORG

UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6 UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6 This information is current as Shu-Jie Peng, Ran-Ran Yao, Shuang-Shuang Yu, Hong-Yan of September 28, 2021. Chen, Xuewen Pang, Yu Zhang and Jun Zhang J Immunol 2019; 203:1943-1951; Prepublished online 26 August 2019; doi: 10.4049/jimmunol.1800750 http://www.jimmunol.org/content/203/7/1943 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/08/25/jimmunol.180075 Material 0.DCSupplemental http://www.jimmunol.org/ References This article cites 57 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/203/7/1943.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6 Shu-Jie Peng,1 Ran-Ran Yao,1 Shuang-Shuang Yu, Hong-Yan Chen, Xuewen Pang, Yu Zhang, and Jun Zhang Human UBL4A/GdX, encoding an ubiquitin-like protein, was shown in this study to be upregulated by viral infection and IFN stimulation. Then the functions of UBL4A in antiviral immune response were characterized. Overexpression of UBL4A promoted RNA virus–induced ISRE or IFN-b or NF-kB activation, leading to enhanced type I IFN transcription and reduced virus replication. Consistently, knockdown of UBL4A resulted in reduced type I IFN transcription and enhanced virus replication. Additionally, overexpression of UBL4A promoted virus-induced phosphorylation of TBK1, IRF3, and IKKa/b. Knockdown of UBL4A inhibited virus-induced phosphorylation of TBK1, IRF3, and IKKa/b. Coimmunoprecipitation showed that UBL4A interacted with TRAF6, and this interaction was enhanced upon viral infection. Ubiquitination assays showed that UBL4A Downloaded from promoted the K63-linked ubiquitination of TRAF6. Therefore, we reveal a novel positive feedback regulation of UBL4A in innate immune response combating virus invasion by enhancing the K63-linked ubiquitination of TRAF6. The Journal of Immunology, 2019, 203: 1943–1951. iral nucleic acids are sensed by pattern recognition re- promote the production of type I IFNs and proinflammatory ceptors (PRRs) and then induce the production of type I cytokines (24, 25). http://www.jimmunol.org/ V IFNs and proinflammatory cytokines (1, 2). For RNA TNF receptor–associated factor (TRAF) family members have viruses, TLR family member TLR3 senses dsRNA (3, 4), whereas been reported to be essential for the recruitment of the down- TLR7/8 senses ssRNA in the endosomes (5, 6). RIG-I–like re- stream kinases to the adaptor proteins. Among them, TRAF6 is a ceptors (RLRs) recognize viral dsRNA in the cytosol (7–9). For ubiquitin E3 ligase that attaches the K63-linked polyubiquitin DNA viruses, TLR9 senses unmethylated DNA in the endosomes chains on substrate proteins or itself (26). The autoubiquiti- (10). cGMP-AMP (cGAMP) synthase (cGAS) is the main iden- nation at Lys124 of TRAF6 is a key activation step for TRAF6 tified cytosolic viral DNA sensor (CDS) (2, 11). Besides, several (27). It is critical for the recruitment of IKKa/b/g and/or TBK other DNA sensors are reported, including AIM2, DAI, DDX41, complex to adaptor proteins (28, 29). By this, TRAF6 func- IFI16, RNA polymerase III, Lsm14A, etc. (12–17). Upon viral tions as an important signaling scaffold downstream of multiple by guest on September 28, 2021 invasion, viral nucleic acids are recognized by corresponding PRR such as TLRs, NLRs, RLRs, and CDSs, which eventually PRRs and then recruit the downstream adaptor proteins such as leads to the production of proinflammatory cytokines and type I MyD88, TRIF, MAVS, and STING (11, 18–20). Then, the acti- IFNs (19, 30–32). Therefore, the regulation at TRAF6 level vation signals transmitted by different sensors converge at may affect the activation of NF-kB signaling and multiple PRR the common kinase level IKKa/b/g and TBK1 (21–23). Then, signaling. phosphorylated by these kinases, the transcription factors NF-kB, Ubiquitin-like protein 4A (UBL4A)/X-linked gene in the IRF3, and IRF7 are activated and translocate into the nucleus and G6PD cluster at Xq28 (Gdx) was originally identified as a housekeeping gene that shares 43% identity to ubiquitin in the N terminus (33). However, the ubiquitin-related activity of UBL4A is not reported. UBL4A can form a complex with Bag6 and Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory Trc35 and localize to the endoplasmic reticulum (ER) to reg- of Medical Immunology, Ministry of Health (Peking University), Peking University Health Science Center, Beijing 100191, China ulate ER-associated degradation (34). UBL4A participates in the transport of tail-anchored proteins into the ER (35). UBL4A is 1These authors contributed equally to this work. also involved in DNA damage–induced cell death (36). UBL4A ORCIDs: 0000-0003-3074-3908 (S.-J.P.); 0000-0002-2733-0048 (R.-R.Y.). is a potential tumor suppressor by dephosphorylation of Stat3 Received for publication May 29, 2018. Accepted for publication July 24, 2019. via promoting the interaction between Tc45 and Stat3 (37). This work was supported by grants from the National Natural Science Foundation of For Akt activation, UBL4A mediates insulin-induced plasma- China (81873871 and 31470843) and the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT31039). membraned translocation of Akt. UBL4A is also an Arp2/3 Address correspondence and reprint requests to Dr. Jun Zhang, Peking University binding partner and mediates actin branching (38). Until now, Health Science Center, 38 Xue Yuan Road, Hai Dian District, Beijing 100191, China. the functions of UBL4A in antiviral immune response are not E-mail address: [email protected] characterized. The online version of this article contains supplemental material. In the current study, we report that UBL4A is a novel IFN- Abbreviations used in this article: CDS, cytosolic viral DNA sensor; ER, endoplas- stimulated gene (ISG). Overexpression of UBL4A promoted mic reticulum; iBMDM, immortalized bone marrow–derived macrophage; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; NC, negative control; PRR, pattern virus-induced signaling, whereas knockdown of UBL4A had the recognition receptor; RLR, RIG-I–like receptor; SeV, Sendai virus; siRNA, small opposite effects and promoted viral replication. Further studies interfering RNA; TRAF, TNF receptor–associated factor; UBL4A, ubiquitin-like showed that UBL4A physically associated with TRAF6 and protein 4A; VSV, vesicular stomatitis virus. then augment the antiviral immune response by promoting the Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 K63-linked ubiquitination of TRAF6. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800750 1944 POSITIVE REGULATION OF VIRUS-INDUCED SIGNALING BY UBL4A Materials and Methods Ab was added. Finally, ECL assay (ImageQuant LAS 500) was used to Cells, reagents, and plasmids detect the signal. HEK293, HEK293T, HeLa cells, and immortalized bone marrow–derived Coimmunoprecipitation macrophages (iBMDMs) were maintained in DMEM (Thermo Fisher HEK293T cells were seeded at a density of 2.0 3 105 cells/ml in a 10 cm Scientific, Waltham, MA) supplemented with 10% heat-inactivated FBS cell culture dish. After 24 h, the plasmids were transfected into cells. (CellMax) and penicillin (100 U/ml)/streptomycin (100 mg/ml). Lipofectamine The cells were harvested after another 24 h and then lysed for 1 h, and 3000 and Opti-MEM were purchased from Thermo Fisher Scientific. the supernatant was collected. Each sample was coincubated together Poly(I:C) and poly(dA:dT) were purchased from InvivoGen (San Diego, with the indicated Abs or mouse IgG for control overnight. The superna- CA). pENTER-Flag-His-UBL4A was purchased from Vigene Biosciences tant was coincubated together with protein A agarose beads for another (Rockville, MD). HA-tagged UBL4A was constructed by standard 2 h. Centrifugal pellets were washed with washing buffer. The results molecular biology techniques. Human IFN-a was from BioLegend, and were analyzed according to immunoblot analysis. For endogenous im- IFN-b was from PeproTech (Rocky Hill, NJ). munoprecipitation, HEK293 cells were treated with or without SeV infection for 24 h. Then, the cells were harvested, lysed, and immuno- Abs precipitated by IgG control or anti-UBL4A Ab. The blot was monitored Abs specific for p-TBK1, TBK1, p-IRF3, IRF3, p-IKKa/b, TRAF6, by anti-TRAF6 Ab. p-IkBa, and K63-linkage–specific polyubiquitin were purchased from Cell Signaling Technology (Danvers, MA). The TRAF6 Ab used for immu- In vivo ubiquitination assay noprecipitation was from Santa Cruz Biotechnology (Dallas,
Load more

Recommended publications
  • Deciphering the Functions of Ets2, Pten and P53 in Stromal Fibroblasts in Multiple
    Deciphering the Functions of Ets2, Pten and p53 in Stromal Fibroblasts in Multiple Breast Cancer Models DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Julie Wallace Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2013 Dissertation Committee: Michael C. Ostrowski, PhD, Advisor Gustavo Leone, PhD Denis Guttridge, PhD Dawn Chandler, PhD Copyright by Julie Wallace 2013 Abstract Breast cancer is the second most common cancer in American women, and is also the second leading cause of cancer death in women. It is estimated that nearly a quarter of a million new cases of invasive breast cancer will be diagnosed in women in the United States this year, and approximately 40,000 of these women will die from breast cancer. Although death rates have been on the decline for the past decade, there is still much we need to learn about this disease to improve prevention, detection and treatment strategies. The majority of early studies have focused on the malignant tumor cells themselves, and much has been learned concerning mutations, amplifications and other genetic and epigenetic alterations of these cells. However more recent work has acknowledged the strong influence of tumor stroma on the initiation, progression and recurrence of cancer. Under normal conditions this stroma has been shown to have protective effects against tumorigenesis, however the transformation of tumor cells manipulates this surrounding environment to actually promote malignancy. Fibroblasts in particular make up a significant portion of this stroma, and have been shown to impact various aspects of tumor cell biology.
    [Show full text]
  • To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants
    Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Shama K Khokhar M.Sc., Bilaspur University, 2004 B.Sc., Bhopal University, 2002 2007 1 COPYRIGHT SHAMA K KHOKHAR 2007 2 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES Date of Defense: 12-03-07 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY SHAMA KHAN KHOKHAR ENTITLED Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science Madhavi P. Kadakia, Ph.D. Thesis Director Daniel Organisciak , Ph.D. Department Chair Committee on Final Examination Madhavi P. Kadakia, Ph.D. Steven J. Berberich, Ph.D. Michael Leffak, Ph.D. Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies 3 Abstract Khokhar, Shama K. M.S., Department of Biochemistry and Molecular Biology, Wright State University, 2007 Differential effect of TAp63γ mutants on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin.
    [Show full text]
  • The Role of Ubiquitination in NF-Κb Signaling During Virus Infection
    viruses Review The Role of Ubiquitination in NF-κB Signaling during Virus Infection Kun Song and Shitao Li * Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA; [email protected] * Correspondence: [email protected] Abstract: The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions. Keywords: NF-κB; polyubiquitination; linear ubiquitination; inflammation; host defense; viral infection Citation: Song, K.; Li, S. The Role of 1. Introduction Ubiquitination in NF-κB Signaling The nuclear factor κB (NF-κB) is a small family of five transcription factors, including during Virus Infection. Viruses 2021, RelA (also known as p65), RelB, c-Rel, p50 and p52 [1].
    [Show full text]
  • WO 2019/089592 Al 09 May 2019 (09.05.2019) W 1 P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization III International Bureau (10) International Publication Number (43) International Publication Date WO 2019/089592 Al 09 May 2019 (09.05.2019) W 1 P O PCT (51) International Patent Classification: (72) Inventors; and A61K 35/12 (2015.01) C07K 16/30 (2006.01) (71) Applicants: JAN, Max [US/US]; c/o The Broad Institute, A61K 5/7 7 (2015.01) C07K 14/705 (2006.01) Inc., 45 1 Main Street, Cambridge, Massachusetts 02142 (US). SIEVERS, Quinlan [US/US]; c/o The Broad In¬ (21) International Application Number: stitute, Inc., 451 Main Street, Cambridge, Massachusetts PCT/US2018/058210 02142 (US). EBERT, Benjamin [US/US]; c/o The Broad (22) International Filing Date: Institute, Inc., 451 Main Street, Cambridge, Massachusetts 30 October 2018 (30. 10.2018) 02142 (US). MAUS, Marcela [US/US]; c/o The Broad In¬ stitute, Inc., 451 Main Street, Cambridge, Massachusetts (25) Filing Language: English 02142 (US). (26) Publication Language: English (74) Agent: COWLES, Christopher R. et al; Burns & Levin- (30) Priority Data: son, LLP, 125 Summer Street, Boston, Massachusetts 62/579,454 3 1 October 2017 (3 1. 10.2017) U S 021 10 (US). 62/633,725 22 February 2018 (22.02.2018) U S (81) Designated States (unless otherwise indicated, for every (71) Applicants: THE GENERAL HOSPITAL CORPO¬ kind of national protection available): AE, AG, AL, AM, RATION [US/US]; 55 Fruit Street, Boston, Massachu¬ AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, setts 021 14 (US) BRIGHAM & WOMEN'S HOSPITAL CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, [US/US]; 75 Francis Street, Boston, Massachusetts 021 15 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (US) PRESIDENT AND FELLOWS OF HARVARD HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, COLLEGE [US/US]; 17 Quincy Street, Cambridge, Mass¬ KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, achusetts 02138 (US).
    [Show full text]
  • The Role of the Transmembrane RING Finger Proteins in Cellular and Organelle Function
    Membranes 2011, 1, 354-393; doi:10.3390/membranes1040354 OPEN ACCESS membranes ISSN 2077-0375 www.mdpi.com/journal/membranes Review The Role of the Transmembrane RING Finger Proteins in Cellular and Organelle Function Nobuhiro Nakamura Department of Biological Sciences, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan; E-Mail: [email protected]; Tel.: +81-45-924-5726; Fax: +81-45-924-5824 Received: 26 October 2011; in revised form: 24 November 2011 / Accepted: 5 December 2011 / Published: 9 December 2011 Abstract: A large number of RING finger (RNF) proteins are present in eukaryotic cells and the majority of them are believed to act as E3 ubiquitin ligases. In humans, 49 RNF proteins are predicted to contain transmembrane domains, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways, as well as to mitochondria and peroxisomes. They are thought to be molecular regulators of the organization and integrity of the functions and dynamic architecture of cellular membrane and membranous organelles. Emerging evidence has suggested that transmembrane RNF proteins control the stability, trafficking and activity of proteins that are involved in many aspects of cellular and physiological processes. This review summarizes the current knowledge of mammalian transmembrane RNF proteins, focusing on their roles and significance. Keywords: endocytosis; ERAD; immune regulation; membrane trafficking; mitochondrial dynamics; proteasome; quality control; RNF; ubiquitin; ubiquitin ligase 1. Introduction Ubiquitination is a posttranslational modification that mediates the covalent attachment of ubiquitin (Ub), a small, highly conserved, cytoplasmic protein of 76 amino acid residues, to target proteins.
    [Show full text]
  • RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma
    cancers Article RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma Jing Gao, Yang Wang, Jie Yang, Weixia Zhang, Kun Meng, Yue Sun, Yangjia Li and Qing-Yu He * Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; [email protected] (J.G.); [email protected] (Y.W.); [email protected] (J.Y.); [email protected] (W.Z.); [email protected] (K.M.); [email protected] (Y.S.); [email protected] (Y.L.) * Correspondence: [email protected]; Tel.: +86-20-85227039; Fax: +86-20-85227039 Received: 5 May 2019; Accepted: 12 June 2019; Published: 18 June 2019 Abstract: Background: The prognosis of esophageal squamous cell carcinoma (ESCC) is generally poor, and the identification of molecular markers related to the regulation of ESCC invasion and migration is important. Methods and Results: In this study, we report that ring finger protein-128 (RNF128) enhances the invasiveness and motility of ESCC cells by using transwell assays and Western blotting. A xenograft nude mouse model showed that RNF128 promotes the metastasis of ESCC cells in the lung. A signal pathway analysis identified the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/matrix matalloproteinases 2 (MMP-2) cascade as a mediator of RNF128-induced enhancement of ESCC progression. Inhibition experiments using inhibitors of EGFR, ERK kinase (MEK)/extracellular-signal-regulated-kinase (ERK), and MMP-2 reversed this progression. Co-immunoprecipitation demonstrated that RNF128 promotes the activation of the EGFR/ERK/MMP-2 pathway by interacting with p53 and p53 interacting with EGFR.
    [Show full text]
  • Fibroblasts from the Human Skin Dermo-Hypodermal Junction Are
    cells Article Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling Valérie Haydont 1,*, Véronique Neiveyans 1, Philippe Perez 1, Élodie Busson 2, 2 1, 3,4,5,6, , Jean-Jacques Lataillade , Daniel Asselineau y and Nicolas O. Fortunel y * 1 Advanced Research, L’Oréal Research and Innovation, 93600 Aulnay-sous-Bois, France; [email protected] (V.N.); [email protected] (P.P.); [email protected] (D.A.) 2 Department of Medical and Surgical Assistance to the Armed Forces, French Forces Biomedical Research Institute (IRBA), 91223 CEDEX Brétigny sur Orge, France; [email protected] (É.B.); [email protected] (J.-J.L.) 3 Laboratoire de Génomique et Radiobiologie de la Kératinopoïèse, Institut de Biologie François Jacob, CEA/DRF/IRCM, 91000 Evry, France 4 INSERM U967, 92260 Fontenay-aux-Roses, France 5 Université Paris-Diderot, 75013 Paris 7, France 6 Université Paris-Saclay, 78140 Paris 11, France * Correspondence: [email protected] (V.H.); [email protected] (N.O.F.); Tel.: +33-1-48-68-96-00 (V.H.); +33-1-60-87-34-92 or +33-1-60-87-34-98 (N.O.F.) These authors contributed equally to the work. y Received: 15 December 2019; Accepted: 24 January 2020; Published: 5 February 2020 Abstract: Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology.
    [Show full text]
  • Inhibitory Receptor Agonists: the Future of Autoimmune Disease Therapeutics?
    Available online at www.sciencedirect.com ScienceDirect Inhibitory receptor agonists: the future of autoimmune disease therapeutics? 1,2 1 Stephanie Grebinoski and Dario AA Vignali + Central and peripheral tolerance both contribute to protection Tregs, implying that >30% of CD4 effectors could be against autoimmunity. The pathogenesis of autoimmunity, autoreactive [2 ]. Critical deficits or limitations in toler- however, can result from critical deficits or limitations in ance mechanisms, rather than complete failure, can con- peripheral and/or central tolerance mechanisms, presenting an tribute to autoimmunity (Figure 1). Evidence suggests opportunity for therapeutic intervention. Recent advances that the majority of these deficits affect peripheral toler- highlight the substantial impact of inhibitory receptors (IRs), ance, presenting an opportunity for therapeutic interven- which mediate peripheral tolerance, in autoimmunity. Deletion tion [1]. and blockade studies in mice, IR disruption in humans, and correlation with positive disease outcomes all highlight Recent advances in cancer immunotherapy indicate that IR potential clinical benefits of enhancing IR signaling modulation affects T cell function and disease outcome, (agonism) — specifically CTLA4, PD1, LAG3, TIM3 and which merited the 2018 Nobel Prize in Medicine [3]. IRs TIGIT — to treat autoimmune disease. Although critical mediateperipheral tolerance byantagonizing T cell receptor questions remain, IR agonists represent an unappreciated and (TCR) signaling and/or signal propagation in autoreactive T untapped opportunity for the treatment of autoimmune and cells, resulting in a dysfunctional state [4]. Evolutionarily, inflammatory diseases. IRs are upregulated in response TCR signaling to dampen the immune response post infection or upon recognition of Addresses self-antigen(Figure1). Under chronic conditions, IR expres- 1 Department of Immunology, University of Pittsburgh School of sion is heightened and T cell effector function is inhibited Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA 2 [5].
    [Show full text]
  • Single-Cell RNA Sequencing Identifies Candidate Renal
    BASIC RESEARCH www.jasn.org Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species Kurt A. Zimmerman,1 Melissa R. Bentley,1 Jeremie M. Lever ,2 Zhang Li,1 David K. Crossman,3 Cheng Jack Song,1 Shanrun Liu,4 Michael R. Crowley,3 James F. George,5 Michal Mrug,2,6 and Bradley K. Yoder1 1Department of Cell, Developmental, and Integrative Biology, 2Division of Nephrology, Department of Medicine, 3Department of Genetics, 4Department of Biochemistry and Molecular Genetics, and 5Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; and 6Department of Veterans Affairs Medical Center, Birmingham, Alabama ABSTRACT Background Resident macrophages regulate homeostatic and disease processes in multiple tissues, in- cluding the kidney. Despite having well defined markers to identify these cells in mice, technical limita- tions have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients. Methods As an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell–negative CD45+ innate immune cells in mouse, rat, pig, and human kidney tissue. Results We identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages.
    [Show full text]
  • An Update on the Role of Ubiquitination in Melanoma Development and Therapies
    Journal of Clinical Medicine Review An Update on the Role of Ubiquitination in Melanoma Development and Therapies Frédéric Soysouvanh 1,†, Serena Giuliano 1,† , Nadia Habel 1,†, Najla El-Hachem 2 ,Céline Pisibon 1, Corine Bertolotto 1,3,‡ and Robert Ballotti 1,4,*,‡ 1 Inserm U1065, C3M, Team 1, Biology, and Pathologies of Melanocytes, University of Nice Côte d’Azur, 06200 Nice, France; [email protected] (F.S.); [email protected] (S.G.); [email protected] (N.H.); [email protected] (C.P.); [email protected] (C.B.) 2 Laboratory of Cancer Signaling, University of Liège, 4020 Liège, Belgium; [email protected] 3 Equipe labellisée Fondation ARC 2019, 06200 Nice, France 4 Equipe labellisée Ligue Contre le Cancer 2020, 06200 Nice, France * Correspondence: [email protected]; Tel.: +33-4-89-06-43-32 † Equal contribution. ‡ Equal contribution. Abstract: The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cuta- neous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research Citation: Soysouvanh, F.; Giuliano, have been investigated to find new therapeutic targets for improving patient outcomes. Because of S.; Habel, N.; El-Hachem, N.; Pisibon, the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to C.; Bertolotto, C.; Ballotti, R.
    [Show full text]
  • Master Regulator Analysis of the SARS-Cov-2/Human Interactome
    Journal of Clinical Medicine Article Master Regulator Analysis of the SARS-CoV-2/Human Interactome 1, 2, 2 2, Pietro H. Guzzi y, Daniele Mercatelli y , Carmine Ceraolo and Federico M. Giorgi * 1 Department of Surgical and Medical Science, University of Catanzaro, 88100 Catanzaro, Italy; [email protected] 2 Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; [email protected] (D.M.); [email protected] (C.C.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 28 February 2020; Accepted: 28 March 2020; Published: 1 April 2020 Abstract: The recent epidemic outbreak of a novel human coronavirus called SARS-CoV-2 causing the respiratory tract disease COVID-19 has reached worldwide resonance and a global effort is being undertaken to characterize the molecular features and evolutionary origins of this virus. In this paper, we set out to shed light on the SARS-CoV-2/host receptor recognition, a crucial factor for successful virus infection. Based on the current knowledge of the interactome between SARS-CoV-2 and host cell proteins, we performed Master Regulator Analysis to detect which parts of the human interactome are most affected by the infection. We detected, amongst others, affected apoptotic and mitochondrial mechanisms, and a downregulation of the ACE2 protein receptor, notions that can be used to develop specific therapies against this new virus. Keywords: coronavirus; bioinformatics; gene network analysis; COVID-19; SARS-CoV-2 1. Introduction Beta-coronaviruses are a subgroup of the coronavirus family, large enveloped positive-stranded RNA viruses able to infect a wide variety of mammals and avian species, causing mainly respiratory or enteric diseases [1].
    [Show full text]
  • 1Whb Lichtarge Lab 2006
    Pages 1–5 1whb Evolutionary trace report by report maker January 2, 2010 4.3.3 DSSP 4 4.3.4 HSSP 4 4.3.5 LaTex 4 4.3.6 Muscle 4 4.3.7 Pymol 4 4.4 Note about ET Viewer 5 4.5 Citing this work 5 4.6 About report maker 5 4.7 Attachments 5 1 INTRODUCTION From the original Protein Data Bank entry (PDB id 1whb): Title: Solution structure of the rhodanese-like domain in human ubiquitin specific protease 8 (ubp8) Compound: Mol id: 1; molecule: kiaa0055; chain: a; fragment: rhodanese-like domain; synonym: ubiquitin specific protease 8, ubp8; ec: 3.1.2.15; engineered: yes Organism, scientific name: Homo Sapiens; 1whb contains a single unique chain 1whbA (157 residues long). This is an NMR-determined structure – in this report the first model in the file was used. CONTENTS 1 Introduction 1 2 CHAIN 1WHBA 2.1 P40818 overview 2 Chain 1whbA 1 2.1 P40818 overview 1 From SwissProt, id P40818, 98% identical to 1whbA: 2.2 Multiple sequence alignment for 1whbA 1 Description: Ubiquitin carboxyl-terminal hydrolase 8 (EC 3.1.2.15) 2.3 Residue ranking in 1whbA 1 (Ubiquitin thiolesterase 8) (Ubiquitin-specific processing protease 8) 2.4 Top ranking residues in 1whbA and their position on (Deubiquitinating enzyme 8) (hUBPy). the structure 2 Organism, scientific name: Homo sapiens (Human). 2.4.1 Clustering of residues at 26% coverage. 2 Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; 2.4.2 Possible novel functional surfaces at 26% Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; coverage.
    [Show full text]