DOCSLIB.ORG

Immunity and Disease Mechanisms of Jak/STAT Signaling In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immunity and Disease Mechanisms of Jak/STAT Signaling In Mechanisms of Jak/STAT Signaling in Immunity and Disease Alejandro V. Villarino, Yuka Kanno, John R. Ferdinand and John J. O'Shea This information is current as of October 2, 2021. J Immunol 2015; 194:21-27; ; doi: 10.4049/jimmunol.1401867 http://www.jimmunol.org/content/194/1/21 Downloaded from References This article cites 73 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/1/21.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Mechanisms of Jak/STAT Signaling in Immunity and Disease Alejandro V. Villarino, Yuka Kanno, John R. Ferdinand, and John J. O’Shea More than two decades ago, experiments on the antivi- Specificity and redundancy in Jak/STAT signaling ral mechanisms of IFNs led to the discovery of JAKs and The biochemistry of Jak/STAT signaling has been studied their downstream effectors, the STAT proteins. This extensively (2). Briefly, signaling begins with extracellular pathway has since become a paradigm for membrane- association of cytokines or growth factors with their corre- to-nucleus signaling and explains how a broad range sponding transmembrane receptors. This facilitates trans-ac- of soluble factors, including cytokines and hormones, tivation of receptor-bound Jaks by putting them in spatial mediate their diverse functions. Jak/STAT research proximity and by prompting conformational changes that has not only impacted basic science, particularly in the distance their kinase domains from inhibitory pseudokinase Downloaded from context of intercellular communication and cell-extrinsic domains (3). Activated Jaks then phosphorylate latent STAT control of gene expression, it also has become a proto- monomers, leading to dimerization, nuclear translocation, type for transition from bench to bedside, culminating and DNA binding (Fig. 1). In mammals, four Jaks (JAK1, in the development and clinical implementation of JAK2, JAK3, TYK2) and seven STATs (STAT1, STAT2, pathway-specific therapeutics. This brief review synthe- STAT3, STAT4, STAT5a, STAT5b, STAT6) are used by . sizes our current understanding of Jak/STAT biology 50 cytokines and growth factors, raising the question of http://www.jimmunol.org/ while taking stock of the lessons learned and the chal- how specificity is achieved with so few building blocks. One lenges that lie ahead. The Journal of Immunology, explanation is that specificity is lineage dependent, meaning 2015, 194: 21–27. that cytokines that activate the same STATs may operate on different cell types (or states), each with distinct panels of STAT-sensitive genes. However, this does not explain why etazoans, and even unicellular aggregates, must cytokines that “look” similar in terms of STAT-signaling coordinate the diverse activities of cellular hordes cascades can have different outcomes within the same cell to achieve collective goals. This imperative underlies type or state. A classic example of this dichotomy is the case of M by guest on October 2, 2021 two fundamental questions in biology: how do individual IL-6 and IL-10; both are potent STAT3 activators in myeloid cells sense external cues and, in turn, how are these external cells, but the former exerts mostly proinflammatory effects, cues interpreted to program behavior? Evolution has provided whereas the latter is mostly anti-inflammatory. There is evi- a number of elegant solutions; among these, the Jak/STAT dence that qualitative differences in the duration and or in- pathway has emerged as a paradigm, as evidenced by its con- tensity of STAT3 signaling underlie the disparity, but this servation across phylogeny from vertebrates to lower organ- may not be the whole story (4). Another point to consider is isms like Dictyostelium (1). Not surprisingly, the study of that, although each cytokine is traditionally associated with this ancient pathway has yielded fundamental insights about a particular STAT, almost all engage more than one family cellular communication and the role of membrane-to- member to varying degrees (i.e., heterogeneous signaling; nucleus signaling in controlling gene expression. It also has Fig. 1). For example, type I IFNs are prototypical STAT1 shaped our understanding of the mammalian immune sys- activators but also activate STAT3 and STAT4 (5). In some tem, perhaps the most intricate of all cellular networks, and instances, cytokines engage multiple STATs with comparable provided both the impetus and rationale for pathway- potency, as with IL-27, a strong activator of both STAT1 and specific therapeutics. This brief review discusses current STAT3 (6), whereas in others there is clear hierarchy, as with theories on how Jak/STAT signaling works at the cellular, IFN-g, which elicits a strong STAT1 response coupled to molecular, and genomic levels, with particular emphasis a relatively weak STAT3 response (7). This heterogeneity is on human disease. Our aim is not to be expansive but, philosophically satisfying because graded combinations of rather, to highlight emerging ideas and to present a modern STATs may contribute to cytokine specificity, although it is view of Jak/STAT research as it strides forward into its third also unlikely that such quantitative differences account for all decade. of it. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Mus- Skin Diseases, National Institutes of Health, Building 10, Room 13C103C, 10 Center culoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 Drive, Bethesda, MD 20892. E-mail address: [email protected] Received for publication July 30, 2014. Accepted for publication September 25, 2014. Abbreviations used in this article: GAS, IFN-g activation site; GWAS, genome-wide association study; lncRNA, long noncoding RNA; miRNA, microRNA; SNP, single Address correspondence and reprint requests to Dr. John J. O’Shea, Molecular Immu- nucleotide polymorphism; TF, transcription factor. nology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401867 22 BRIEF REVIEWS: MECHANISMS OF JAK/STAT SIGNALING Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 FIGURE 1. Canonical Jak/STAT signaling begins with the association of cytokines and their corresponding transmembrane receptors. This brings Jaks in proximity, leading to phosphorylation of both the Jaks themselves and the cytoplasmic tails of the receptors, creating requisite docking sites for latent STAT monomers. STAT p-Tyr then proceeds as the major activating event, leading to dimerization, translocation, DNA binding, and target gene induction. Noncanonical deviations from this model also should be considered. First, p-Tyr can occur via Jak-independent pathways and, in fact, is not required for some activities (unphosphorylated STATs). Additional posttranslational modifications (e.g., p-Ser) also can influence STATs. Next, although each cytokine/receptor is typically associated with a particular STAT, most engage more than one family member (heterogeneous signaling), leading to the formation of homodimers, as wellas heterodimers and higher-order tetramers. These migrate to the nucleus where they bind to DNA through consensus GAS elements, as well as through GAS- independent mechanisms, leading to induction, repression, or neutral binding of protein-coding (mRNAs) or noncoding (miRNAs and lncRNAs) target genes, typically as part of multimolecular complexes. Because of a shared affinity for GAS motifs, multiple STATs may bind to the same target sites (overlapping specificities). They also can bind to and promote remodeling of gene enhancers and regulate the epigenetic status of target genes. Lastly, extranuclear functions have increasingly been recognized, most notably in the mitochondrion. It is well established that STATs can bind directly to DNA, Genome-wide analyses have yielded a number of surprises thus acting as classical transcription factors (TFs). Exactly where about STAT biology. First is the pervasive nature of STAT and how they bind are matters of ongoing debate. Traditionally, binding. In Th cells, thousands of binding sites have been these questions have been addressed using low-throughput, mapped for each family member, sometimes proximal to candidate-driven approaches but, with the advent of next- transcriptional start sites, as would have been predicted, but generation sequencing, it is now possible to tackle them on a more often distal, typically associated with enhancers or other genome-wide scale. Most notably, deep sequencing can be cis-regulatory elements (10). Many of these binding events are coupled with chromatin immunoprecipitation to produce com- not associated with consensus DNA motifs (i.e.,
Load more

Recommended publications
  • Expression of the Tumor Necrosis Factor Receptor-Associated Factors
    Expression of the Tumor Necrosis Factor Receptor- Associated Factors (TRAFs) 1 and 2 is a Characteristic Feature of Hodgkin and Reed-Sternberg Cells Keith F. Izban, M.D., Melek Ergin, M.D, Robert L. Martinez, B.A., HT(ASCP), Serhan Alkan, M.D. Department of Pathology, Loyola University Medical Center, Maywood, Illinois the HD cell lines. Although KMH2 showed weak Tumor necrosis factor receptor–associated factors expression, the remaining HD cell lines also lacked (TRAFs) are a recently established group of proteins TRAF5 protein. These data demonstrate that consti- involved in the intracellular signal transduction of tutive expression of TRAF1 and TRAF2 is a charac- several members of the tumor necrosis factor recep- teristic feature of HRS cells from both patient and tor (TNFR) superfamily. Recently, specific members cell line specimens. Furthermore, with the excep- of the TRAF family have been implicated in promot- tion of TRAF1 expression, HRS cells from the three ing cell survival as well as activation of the tran- HD cell lines showed similar TRAF protein expres- ␬ scription factor NF- B. We investigated the consti- sion patterns. Overall, these findings demonstrate tutive expression of TRAF1 and TRAF2 in Hodgkin the expression of several TRAF proteins in HD. Sig- and Reed–Sternberg (HRS) cells from archived nificantly, the altered regulation of selective TRAF paraffin-embedded tissues obtained from 21 pa- proteins may reflect HRS cell response to stimula- tients diagnosed with classical Hodgkin’s disease tion from the microenvironment and potentially (HD). In a selective portion of cases, examination of contribute both to apoptosis resistance and cell HRS cells for Epstein-Barr virus (EBV)–encoded maintenance of HRS cells.
    [Show full text]
  • Computational Modeling of Lysine Post-Translational Modification: an Overview Md
    c and S eti ys h te nt m y s S B Hasan MM et al., Curr Synthetic Sys Biol 2018, 6:1 t i n o e l Current Synthetic and o r r g DOI: 10.4172/2332-0737.1000137 u y C ISSN: 2332-0737 Systems Biology CommentaryResearch Article OpenOpen Access Access Computational Modeling of Lysine Post-Translational Modification: An Overview Md. Mehedi Hasan 1*, Mst. Shamima Khatun2, and Hiroyuki Kurata1,3 1Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka, Fukuoka 820-8502, Japan 2Department of Statistics, Laboratory of Bioinformatics, Rajshahi University-6205, Bangladesh 3Biomedical Informatics R&D Center, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka, Fukuoka 820-8502, Japan Commentary hot spot for PTMs, and a number of protein lysine modifications could occur in both histone and non-histone proteins [11,12]. For instance, Living organisms have a magnificent ordered and complex lysine methylation in non-histone proteins can regulate the protein structure. In regulating the cellular functions, post-translational activity and protein structure stability [13]. In 2004, the Nobel Prize in modifications (PTMs) are critical molecular measures. They alter Chemistry was awarded jointly to Aaron Ciechanover, Avram Hershko protein conformation, modulating their activity, stability and and Irwin Rose for the discovery of lysine ubiquitin-mediated protein localization. Up to date, more than 300 types of PTMs are experimentally degradation [14]. discovered in vivo and in vitro pathways [1,2]. Major and common PTMs are methylation, ubiquitination, succinylation, phosphorylation, Moreover, in biological process, lysine can be modified by the glycosylation, acetylation, and sumoylation.
    [Show full text]
  • P53 Acetylation: Regulation and Consequences
    Cancers 2015, 7, 30-69; doi:10.3390/cancers7010030 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review p53 Acetylation: Regulation and Consequences Sara M. Reed 1,2 and Dawn E. Quelle 1,2,3,* 1 Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; E-Mail: [email protected] 2 Medical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA 3 Department of Pathology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-319-353-5749; Fax: +1-319-335-8930. Academic Editor: Rebecca S. Hartley Received: 18 March 2014 / Accepted: 12 December 2014 / Published: 23 December 2014 Abstract: Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites) as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis) to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post-translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression.
    [Show full text]
  • Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer
    H OH metabolites OH Review Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer Mio Harachi 1, Kenta Masui 1,* , Webster K. Cavenee 2, Paul S. Mischel 3 and Noriyuki Shibata 1 1 Department of Pathology, Division of Pathological Neuroscience, Tokyo Women’s Medical University, Tokyo 162-8666, Japan; [email protected] (M.H.); [email protected] (N.S.) 2 Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA; [email protected] 3 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; [email protected] * Correspondence: [email protected]; Tel.: +81-3-3353-8111; Fax: +81-3-5269-7408 Abstract: Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unex- pectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments.
    [Show full text]
  • TRAF6, a Molecular Bridge Spanning Adaptive Immunity, Innate Immunity and Osteoimmunology Hao Wu1* and Joseph R
    Review articles TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology Hao Wu1* and Joseph R. Arron2 Summary receptor/Toll-like receptor (IL-1R/TLR) superfamily. Gene Tumor necrosis factor (TNF) receptor associated factor targeting experiments have identified several indispen- 6 (TRAF6) is a crucial signaling molecule regulating a sable physiological functions of TRAF6, and structural diverse array of physiological processes, including and biochemical studies have revealed the potential adaptive immunity, innate immunity, bone metabolism mechanisms of its action. By virtue of its many signaling and the development of several tissues including lymph roles, TRAF6 represents an important target in the regu- nodes, mammary glands, skin and the central nervous lation of many disease processes, including immunity, system. It is a member of a group of six closely related inflammation and osteoporosis. BioEssays 25:1096– TRAF proteins, which serve as adapter molecules, coupl- 1105, 2003. ß 2003 Wiley Periodicals, Inc. ing the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 is unique in that, in addition to mediating TNFR family Introduction signaling, it is also essential for signaling downstream of The tumor necrosis factor (TNF) receptor associated factors an unrelated family of receptors, the interleukin-1 (IL-1) (TRAFs) were first identified as two intracellular proteins, TRAF1 and TRAF2, associated with TNF-R2,(1) a member of 1Department of Biochemistry, Weill Medical College of Cornell the TNF receptor (TNFR) superfamily. There are currently six University, New York. mammalian TRAFs (TRAF1-6), which have emerged as 2Tri-Institutional MD-PhD Program, Weill Medical College of Cornell important proximal signal transducers for the TNFR super- University, New York.
    [Show full text]
  • Control of Smad7 Stability by Competition Between Acetylation and Ubiquitination
    Molecular Cell, Vol. 10, 483–493, September, 2002, Copyright 2002 by Cell Press Control of Smad7 Stability by Competition between Acetylation and Ubiquitination Eva Gro¨ nroos, Ulf Hellman, Carl-Henrik Heldin, 1998), where it binds the receptors and inhibits further and Johan Ericsson1 signaling by at least two different mechanisms. First, Ludwig Institute for Cancer Research Smad7 is able to interfere with TGF␤ signaling by Box 595 blocking the interactions between the R-Smads and the Husargatan 3 activated receptors (Hayashi et al., 1997; Nakao et al., S-751 24 Uppsala 1997). Second, Smad7 interacts with the E3-ubiquitin Sweden ligases Smurf1 or Smurf2 in the nucleus; after TGF␤ stimulation, the Smad7-Smurf complex translocates from the nucleus to the plasma membrane, where Smurf Summary induces ubiquitination and degradation of the TGF␤ re- ceptors (Ebisawa et al., 2001; Kavsak et al., 2000). Smad proteins regulate gene expression in response Acetylation is a dynamic posttranslational modifica- to TGF␤ signaling. Here we present evidence that tion of lysine residues. Proteins with intrinsic histone Smad7 interacts with the transcriptional coactivator acetyltransferase (HAT) activity act as transcriptional p300, resulting in acetylation of Smad7 on two lysine coactivators by acetylating histones and thereby induce residues in its N terminus. Acetylation or mutation of an open chromatin conformation, which allows the tran- these lysine residues stabilizes Smad7 and protects scriptional machinery access to promoters (Roth et al., it from TGF␤-induced degradation. Furthermore, we 2001). The best characterized HATs are p300, CBP, and demonstrate that the acetylated residues in Smad7 P/CAF (Roth et al., 2001).
    [Show full text]
  • High Levels of Soluble Herpes Virus Entry Mediator in Sera of Patients with Allergic and Autoimmune Diseases
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 35, No. 6, 501-508, December 2003 High levels of soluble herpes virus entry mediator in sera of patients with allergic and autoimmune diseases Hyo Won Jung1, Su Jin La1, Ji Young Kim2 neutrophils and dendritic cells. In three-way MLR, Suk Kyeung Heo1, Ju Yang Kim1, Sa Wang3 mAb 122 and 139 were agonists and mAb 108 had Kack Kyun Kim4, Ki Man Lee5, Hong Rae Cho6 blocking activity. An ELISA was developed to detect Hyeon Woo Lee1, Byungsuk Kwon1 sHVEM in patient sera. sHVEM levels were elevated 1 1,7,8 in sera of patients with allergic asthma, atopic Byung Sam Kim and Byoung Se Kwon dermatitis and rheumatoid arthritis. The mAbs dis- 1 cussed here may be useful for studies of the role The Immunomodulation Research Center and of HVEM in immune responses. Detection of soluble Department of Biological Sciences HVEM might have diagnostic and prognostic value University of Ulsan, Ulsan 680-749, Korea in certain immunological disorders. 2The Immunomics Inc. Ulsan 680-749, Korea Keywords: asthma; atopic; autoimmune diseases; der- 3Department of Microbiology and Immunology matitis; inflammation mediators; rheumatoid arthritis; Indiana University School of Medicine tumor necrosis factor Indianapolis, IN 46202, USA 4Department of Oral Microbiology College of Dentistry, Seoul National University Seoul 110-744, Korea Introduction 5Department of Internal Medicine Members of the tumor necrosis factor receptor Ulsan University Hospital, University of Ulsan (TNFR) superfamily share a similar architecture of Ulsan 682-714, Korea their extracellular domain; this consists of a series of 6Department of Surgery cysteine-rich segments containing 30-40 amino acids Ulsan University Hospital, University of Ulsan with six cysteines in each segment (Mallett et al., Ulsan 682-714, Korea 7 1991).
    [Show full text]
  • Traf5 Is Differentially Expressed in High-Grade Serous Ovarian Cancer And
    1 Traf5 is differentially expressed in high-grade serous ovarian cancer and based on patient survival. 2 3 Shahan Mamoor1 4 [email protected] East Islip, NY 11730 5 High-grade serous ovarian cancer (HGSC) is the most common type of the most lethal 6 gynecologic malignancy (1). To identify genes whose expression was specifically perturbed in HGSC, we used published microarray data (2, 3) to compare the global gene expression 7 profiles of primary HGSC tumors to normal ovarian tissue. We found that the TNF receptor 8 associated factor 5 (TRAF5) (4, 5) was among the genes most differentially expressed in HGSC tumors relative to the normal ovary. In a separate dataset from patients enrolled in the ICON7 9 trial (6), the Traf5 gene was among those most differentially expressed when comparing HGSC tumor gene expression based on patient survival outcomes. Traf5 may be relevant to the 10 biology of high-grade serous ovarian cancers. 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Keywords: ovarian cancer, high-grade serous ovarian cancer, HGSC, targeted therapeutics in 28 ovarian cancer, systems biology of ovarian cancer. 1 OF 13 1 High-grade serous ovarian cancer (HGSC) is the most prevalent type of the most lethal 2 gynecologic malignancy: ovarian cancer (1, 7, 8). The five-year survival rate for women 3 diagnosed with high-grade serous ovarian cancer is between 30-40% and has not changed 4 significantly in decades (7, 8). Understanding how the gene expression of tumors differs from 5 the organ from which it is derived can provide insight into the mechanisms by which cancers 6 are initiated and maintained.
    [Show full text]
  • Acetylation Promotes Tyrrs Nuclear Translocation to Prevent Oxidative Damage
    Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage Xuanye Caoa,1, Chaoqun Lia,1, Siyu Xiaoa,1, Yunlan Tanga, Jing Huanga, Shuan Zhaoa, Xueyu Lia, Jixi Lia, Ruilin Zhanga, and Wei Yua,2 aState Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, People’s Republic of China Edited by Wei Gu, Columbia University, New York, NY, and accepted by Editorial Board Member Carol Prives December 9, 2016 (received for review May 26, 2016) Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential investigated in recent years (9–12). Acetylation regulates diverse aminoacylation function in protein synthesis. Recently, TyrRS has cellular processes, including gene silencing (13), oxidative stress been shown to translocate to the nucleus and protect against DNA (13, 14), DNA repair (15), cell survival and migration (16, 17), and damage due to oxidative stress. However, the mechanism of TyrRS metabolism (9, 18, 19). Most acetylated proteins act as transcrip- nuclear localization has not yet been determined. Herein, we report tion factors in the nucleus and as metabolic enzymes outside the that TyrRS becomes highly acetylated in response to oxidative nucleus (9). Strikingly, the acetylation of multiple aminoacyl- stress, which promotes nuclear translocation. Moreover, p300/ tRNA synthetases, including tyrosyl-tRNA synthetase, has been CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 reported in a number of proteomic studies (10, 12). However, the + (SIRT1), a NAD -dependent deacetylase, regulate the nuclear local- link between acetylation and AARS remains to be established. ization of TyrRS in an acetylation-dependent manner.
    [Show full text]
  • Parps and ADP-Ribosylation: Recent Advances Linking Molecular Functions to Biological Outcomes
    Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Rebecca Gupte,1,2 Ziying Liu,1,2 and W. Lee Kraus1,2 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 2Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA The discovery of poly(ADP-ribose) >50 years ago opened units derived from β-NAD+ to catalyze the ADP-ribosyla- a new field, leading the way for the discovery of the tion reaction. These enzymes include bacterial ADPRTs poly(ADP-ribose) polymerase (PARP) family of enzymes (e.g., cholera toxin and diphtheria toxin) as well as mem- and the ADP-ribosylation reactions that they catalyze. bers of three different protein families in yeast and ani- Although the field was initially focused primarily on the mals: (1) arginine-specific ecto-enzymes (ARTCs), (2) biochemistry and molecular biology of PARP-1 in DNA sirtuins, and (3) PAR polymerases (PARPs) (Hottiger damage detection and repair, the mechanistic and func- et al. 2010). Surprisingly, a recent study showed that the tional understanding of the role of PARPs in different bio- bacterial toxin DarTG can ADP-ribosylate DNA (Jankevi- logical processes has grown considerably of late. This has cius et al. 2016). How this fits into the broader picture of been accompanied by a shift of focus from enzymology to cellular ADP-ribosylation has yet to be determined.
    [Show full text]
  • Lysine Residues Control the Conformational Dynamics of Beta 2-Glycoprotein I
    Showcasing research from the Group of Prof. Mihaela Delcea As featured in: at the University of Greifswald, Germany Lysine residues control the conformational dynamics of beta 2-glycoprotein I Blood protein beta 2-glycoprotein I (beta2GPI) exhibits open and closed conformations and contains many lysine residues, marked in red. In the present work, the potential role of lysine in the conformational dynamics of beta2GPI is investigated. By chemical acetylation of lysine residues, the closed protein conformation opens up as revealed by atomic force microscopy images. Lysine plays a major role in stabilizing the beta2GPI closed conformation as confirmed by lysine charge distribution calculations. See Mihaela Delcea et al., Phys. Chem. Chem. Phys., 2018, 20, 26819. rsc.li/pccp Registered charity number: 207890 PCCP View Article Online PAPER View Journal | View Issue Lysine residues control the conformational dynamics of beta 2-glycoprotein I† Cite this: Phys. Chem. Chem. Phys., 2018, 20,26819 ab ab cde ab Ina Buchholz, Peter Nestler, Susan Ko¨ppen and Mihaela Delcea * One of the major problems in the study of the dynamics of proteins is the visualization of changing conformations that are important for processes ranging from enzyme catalysis to signaling. A protein exhibiting conformational dynamics is the soluble blood protein beta 2-glycoprotein I (beta2GPI), which exists in two conformations: the closed (circular) form and the open (linear) form. It is hypothesized that an increased proportion of the open conformation leads to the autoimmune disease antiphospholipid syndrome (APS). A characteristic feature of beta2GPI is the high content of lysine residues. However, the potential role of lysine in the conformational dynamics of beta2GPI has been poorly investigated.
    [Show full text]
  • Intracellular Signaling Pathways in Rheumatoid Arthritis
    C al & ellu ic la n r li Im C m f u Journal of Malemud, J Clin Cell Immunol 2013, 4:4 o n l o a l n o r DOI: 10.4172/2155-9899.1000160 g u y o J ISSN: 2155-9899 Clinical & Cellular Immunology ReviewResearch Article Article OpenOpen Access Access Intracellular Signaling Pathways in Rheumatoid Arthritis Charles J Malemud* Arthritis Research Laboratory, Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA Abstract Dysfunctional intracellular signaling involving deregulated activation of the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and “cross-talk” between JAK/STAT and the stress-activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK) and Phosphatidylinositide-3-Kinase/AKT/mammalian Target of Rapamycin (PI-3K/AKT/mTOR) pathways play a critical role in rheumatoid arthritis. This is exemplified by immune-mediated chronic inflammation, up-regulated matrix metalloproteinase gene expression, induction of articular chondrocyte apoptosis and “apoptosis-resistance” in rheumatoid synovial tissue. An important consideration in the development of novel therapeutics for rheumatoid arthritis will be the extent to which inhibiting these signal transduction pathways will sufficiently suppress immune cell-mediated inflammation to produce a lasting clinical remission and halt the progression of rheumatoid arthritis pathology. In that regard, the majority of the evidence accumulated over the past decade indicated that merely suppressing pro-inflammatory cytokine-mediated JAK/ STAT, SAPK/MAPK or PI-3K/AKT/mTOR activation in RA patients may be necessary but not sufficient to result in clinical improvement.
    [Show full text]