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https://www.readbyqxmd.com/read/28325627/tlrs-go-linear-on-the-ubiquitin-edge
#1
REVIEW
Julia Zinngrebe, Henning Walczak
Toll-like receptors (TLRs) are crucial in protecting the host from pathogens. However, their exact role in disease remains incompletely understood. TLR signaling is tightly controlled because too little or too much TLR activation can result in immunodeficiency or autoinflammation, respectively. There is increasing evidence that linear ubiquitination, mediated by the linear ubiquitin chain assembly complex (LUBAC), plays a pivotal role in the regulation of TLR signaling. Recent advances have identified an intricate interaction between LUBAC and TLRs, with immunological consequences for infection and the development of autoinflammation in the host...
March 18, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28319114/internally-tagged-ubiquitin-a-tool-to-identify-linear-polyubiquitin-modified-proteins-by-mass-spectrometry
#2
Katarzyna Kliza, Christoph Taumer, Irene Pinzuti, Mirita Franz-Wachtel, Simone Kunzelmann, Benjamin Stieglitz, Boris Macek, Koraljka Husnjak
Ubiquitination controls a plethora of cellular processes. Modifications by linear polyubiquitin have so far been linked with acquired and innate immunity, lymphocyte development and genotoxic stress response. Until now, a single E3 ligase complex (LUBAC), one specific deubiquitinase (OTULIN) and a very few linear polyubiquitinated substrates have been identified. Current methods for studying lysine-based polyubiquitination are not suitable for the detection of linear polyubiquitin-modified proteins. Here, we present an approach to discovering linear polyubiquitin-modified substrates by combining a lysine-less internally tagged ubiquitin (INT-Ub...
March 20, 2017: Nature Methods
https://www.readbyqxmd.com/read/28258062/the-linear-ubiquitin-chain-assembly-complex-regulates-trail-induced-gene-activation-and-cell%C3%A2-death
#3
Elodie Lafont, Chahrazade Kantari-Mimoun, Peter Draber, Diego De Miguel, Torsten Hartwig, Matthias Reichert, Sebastian Kupka, Yutaka Shimizu, Lucia Taraborrelli, Maureen Spit, Martin R Sprick, Henning Walczak
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptosis...
March 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28230260/elevation-of-sharpin-protein-levels-in-prostate-adenocarcinomas-promotes-metastasis-and-impairs-patient-survivals
#4
Hai Huang, Tao Du, Yiming Zhang, Yiming Lai, Kaiwen Li, Xinxing Fan, Dingjun Zhu, Tianxin Lin, Kewei Xu, Jian Huang, Leyuan Liu, Zhenghui Guo
BACKGROUND: SHARPIN, SHANK-associated RH domain interacting protein, associates with a linear ubiquitin chain assembly complex (LUBAC) to regulate inflammation and immunity. It has been reported that SHARPIN is highly expressed in several human tumors including ovarian cancer and liver cancer. We found that SHARPIN is also highly expressed in prostate cancer cell lines of DU145, LNCAP, and PC-3. Suppression of SHARPIN caused an inhibition of NF-κB signal and decreases in tumorigenesis of cultured cells in NOD/SCID mouse model...
May 2017: Prostate
https://www.readbyqxmd.com/read/28165393/reduced-sharpin-and-lubac-formation-may-contribute-to-ccl%C3%A2-or-acetaminophen-induced-liver-cirrhosis-in-mice
#5
Takeshi Yamamotoya, Yusuke Nakatsu, Yasuka Matsunaga, Toshiaki Fukushima, Hiroki Yamazaki, Sunao Kaneko, Midori Fujishiro, Takako Kikuchi, Akifumi Kushiyama, Fuminori Tokunaga, Tomoichiro Asano, Hideyuki Sakoda
Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl₄) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype...
February 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28120397/the-linear-ubiquitin-chain-assembly-complex-acts-as-a-liver-tumor-suppressor-and-inhibits-hepatocyte-apoptosis-and-hepatitis
#6
Yutaka Shimizu, Nieves Peltzer, Alexandra Sevko, Elodie Lafont, Aida Sarr, Helena Draberova, Henning Walczak
Linear ubiquitination is a key post-translational modification that regulates immune signaling and cell death pathways, notably TNFR1 signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex (LUBAC), of which the catalytic core component is HOIP. To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma...
January 24, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28103322/htlv-1-tax-induces-formation-of-the-active-macromolecular-ikk-complex-by-generating-lys63-and-met1-linked-hybrid-polyubiquitin-chains
#7
Yuri Shibata, Fuminori Tokunaga, Eiji Goto, Ginga Komatsu, Jin Gohda, Yasushi Saeki, Keiji Tanaka, Hirotaka Takahashi, Tatsuya Sawasaki, Satoshi Inoue, Hiroyuki Oshiumi, Tsukasa Seya, Hiroyasu Nakano, Yuetsu Tanaka, Kazuhiro Iwai, Jun-Ichiro Inoue
The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is crucial for the development of adult T-cell leukemia (ATL), a highly malignant CD4+ T cell neoplasm. Among the multiple aberrant Tax-induced effects on cellular processes, persistent activation of transcription factor NF-κB, which is activated only transiently upon physiological stimulation, is essential for leukemogenesis. We and others have shown that Tax induces activation of the IκB kinase (IKK) complex, which is a critical step in NF-κB activation, by generating Lys63-linked polyubiquitin chains...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/27903798/the-linear-ubiquitin-assembly-complex-modulates-latent-membrane-protein-1-activation-of-nf-%C3%AE%C2%BAb-and-interferon-regulatory-factor-7
#8
Ling Wang, Yujia Wang, Juan Zhao, Junping Ren, Kenton H Hall, Jonathan P Moorman, Zhi Q Yao, Shunbin Ning
Recently, linear ubiquitin assembly complex (LUBAC)-mediated linear ubiquitination has come into focus due to its emerging role in activation of NF-κB in different biological contexts. However, the role of LUBAC in LMP1 signaling leading to NF-κB and interferon regulatory factor 7 (IRF7) activation has not been investigated. We show here that RNF31, the key component of LUBAC, interacts with LMP1 and IRF7 in Epstein-Barr virus (EBV)-transformed cells and that LUBAC stimulates linear ubiquitination of NEMO and IRF7...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27893701/the-signaling-adaptor-traf1-negatively-regulates-toll-like-receptor-signaling-and-this-underlies-its-role-in-rheumatic-disease
#9
Ali A Abdul-Sater, Maria I Edilova, Derek L Clouthier, Achire Mbanwi, Elisabeth Kremmer, Tania H Watts
TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO...
January 2017: Nature Immunology
https://www.readbyqxmd.com/read/27892465/distinct-role-of-il-1%C3%AE-in-instigating-disease-in-sharpin-cpdm-mice
#10
Prajwal Gurung, Bhesh Raj Sharma, Thirumala-Devi Kanneganti
Mice deficient in SHARPIN (Sharpin(cpdm) mice), a member of linear ubiquitin chain assembly complex (LUBAC), develop severe dermatitis associated with systemic inflammation. Previous studies have demonstrated that components of the TNF-signaling pathway, NLRP3 inflammasome and IL-1R signaling are required to provoke skin inflammation in Sharpin(cpdm) mice. However, whether IL-1α or IL-1β, both of which signals through IL-1R, instigates skin inflammation and systemic disease is not known. Here, we have performed extensive cellular analysis of pre-diseased and diseased Sharpin(cpdm) mice and demonstrated that cellular dysregulation precedes skin inflammation...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27881655/porcine-reproductive-and-respiratory-syndrome-virus-nsp1%C3%AE-inhibits-nf-%C3%AE%C2%BAb-activation-by-targeting-the-linear-ubiquitin-chain-assembly-complex
#11
Huiyuan Jing, Liurong Fang, Zhen Ding, Dang Wang, Wenqi Hao, Li Gao, Wenting Ke, Huanchun Chen, Shaobo Xiao
Linear ubiquitination, a newly discovered posttranslational modification, is catalyzed by the linear ubiquitin chain assembly complex (LUBAC), which is composed of three subunits: one catalytic subunit HOIP and two accessory molecules, HOIL-1L and SHARPIN. Accumulating evidence suggests that linear ubiquitination plays a crucial role in innate immune signaling and especially in the activation of the NF-κB pathway by conjugating linear polyubiquitin chains to NF-κB essential modulator (NEMO, also called IKKγ), the regulatory subunit of the IKK complex...
February 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27857075/linear-ubiquitin-chain-assembly-complex-coordinates-late-thymic-t-cell-differentiation-and-regulatory-t-cell-homeostasis
#12
Charis E Teh, Najoua Lalaoui, Reema Jain, Antonia N Policheni, Melanie Heinlein, Silvia Alvarez-Diaz, Julie M Sheridan, Eva Rieser, Stefanie Deuser, Maurice Darding, Hui-Fern Koay, Yifang Hu, Fiona Kupresanin, Lorraine A O'Reilly, Dale I Godfrey, Gordon K Smyth, Philippe Bouillet, Andreas Strasser, Henning Walczak, John Silke, Daniel H D Gray
The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3(+) regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation...
November 18, 2016: Nature Communications
https://www.readbyqxmd.com/read/27810922/-lubac-deficiency-perturbs-tlr3-signaling-to-cause-immunodeficiency-and-autoinflammation
#13
Julia Zinngrebe, Eva Rieser, Lucia Taraborrelli, Nieves Peltzer, Torsten Hartwig, Hongwei Ren, Ildikó Kovács, Cornelia Endres, Peter Draber, Maurice Darding, Silvia von Karstedt, Johannes Lemke, Balazs Dome, Michael Bergmann, Brian J Ferguson, Henning Walczak
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27786304/survival-of-mature-t-cells-depends-on-signaling-through-hoip
#14
Kazumi Okamura, Akiko Kitamura, Yoshiteru Sasaki, Doo Hyun Chung, Shoji Kagami, Kazuhiro Iwai, Koji Yasutomo
T cell development in the thymus is controlled by a multistep process. The NF-κB pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-κB and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIP(Δlinear) mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4(+) or CD8(+) T cell numbers were markedly reduced with severe defects in NKT cell development...
October 27, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27777308/molecular-determinants-of-scaffold-induced-linear-ubiquitinylation-of-b-cell-lymphoma-leukemia-10-bcl10-during-t-cell-receptor-and-oncogenic-caspase-recruitment-domain-containing-protein-11-card11-signaling
#15
Yong-Kang Yang, Chao Yang, Waipan Chan, Zhaoquan Wang, Katelynn E Deibel, Joel L Pomerantz
The activation of NF-κB downstream of T cell receptor (TCR) engagement is a key signaling step required for normal lymphocyte function during the adaptive immune response. During TCR signaling, the adaptor protein Bcl10 is inducibly recruited to the CARD11 scaffold protein as part of a multicomponent complex that induces IκB kinase (IKK) activity and NF-κB activation. Here, we show that a consequence of this recruitment is the TCR-induced conjugation of Bcl10 with linear-linked polyubiquitin chains to generate the signaling intermediate Lin(Ub)n-Bcl10, which is required for the association of Bcl10 with the NEMO subunit of the IKK complex...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27686184/otulin-deficiency-causes-auto-inflammatory-syndrome
#16
Berthe Katrine Fiil, Mads Gyrd-Hansen
Ubiquitin chains assembled via the N-terminal methionine (Met1 or linear ubiquitin), conjugated by the linear ubiquitin chain assembly complex (LUBAC), participate in NF-κΒ-dependent inflammatory signaling and immune responses. A recent report in Cell finds that OTULIN, a deubiquitinase that selectively cleaves Met1-linked ubiquitin chains, is essential for restraining inflammation in vivo.
November 2016: Cell Research
https://www.readbyqxmd.com/read/27669734/regulation-of-linear-ubiquitin-chain-assembly-complex-by-caspase-mediated-cleavage-of-rnf31
#17
Donghyun Joo, Yong Tang, Marzenna Blonska, Jianping Jin, Xueqiang Zhao, Xin Lin
Cell death and survival signaling pathways have opposed but fundamental functions for various cellular processes and maintain cell homeostasis through cross talk. Here we report a novel mechanism of interaction between these two pathways through the cleavage of RNF31 by caspases. RNF31, a component of the linear ubiquitin chain assembly complex (LUBAC), regulates cell survival by inducing linear ubiquitination of NF-κB signaling components. We found that RNF31 is cleaved under apoptosis conditions through various stimulations...
December 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27591049/spata2-links-cyld-to-lubac-activates-cyld-and-controls-lubac-signaling
#18
Paul R Elliott, Derek Leske, Matous Hrdinka, Katrin Bagola, Berthe K Fiil, Stephen H McLaughlin, Jane Wagstaff, Norbert Volkmar, John C Christianson, Benedikt M Kessler, Stefan M V Freund, David Komander, Mads Gyrd-Hansen
The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains...
September 15, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27572974/shigella-flexneri-suppresses-nf-%C3%AE%C2%BAb-activation-by-inhibiting-linear-ubiquitin-chain-ligation
#19
Maarten F de Jong, Zixu Liu, Didi Chen, Neal M Alto
The linear ubiquitin chain assembly complex (LUBAC) is a multimeric E3 ligase that catalyses M1 or linear ubiquitination of activated immune receptor signalling complexes (RSCs). Mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, but microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri type III secretion system effector E3 ligases IpaH1...
May 27, 2016: Nature Microbiology
https://www.readbyqxmd.com/read/27545878/spata2-mediated-binding-of-cyld-to-hoip-enables-cyld-recruitment-to-signaling-complexes
#20
Sebastian Kupka, Diego De Miguel, Peter Draber, Luigi Martino, Silvia Surinova, Katrin Rittinger, Henning Walczak
Recruitment of the deubiquitinase CYLD to signaling complexes is mediated by its interaction with HOIP, the catalytically active component of the linear ubiquitin chain assembly complex (LUBAC). Here, we identify SPATA2 as a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP. SPATA2 recruitment to TNFR1- and NOD2-signaling complexes is dependent on HOIP, and loss of SPATA2 abolishes CYLD recruitment. Deficiency in SPATA2 exerts limited effects on gene activation pathways but diminishes necroptosis induced by tumor necrosis factor (TNF), resembling loss of CYLD...
August 30, 2016: Cell Reports
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