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LUBAC

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https://www.readbyqxmd.com/read/27903798/lubac-modulates-lmp1-activation-of-nf%C3%AE%C2%BAb-and-irf7
#1
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 NFκB in different biological contexts. However, the role of LUBAC in LMP1 signaling leading to NFκB and IRF7 activation has not been investigated. We have shown here that RNF31, the key component of LUBAC complex, interacts with LMP1 and IRF7 in EBV-transformed cells, and that LUBAC stimualtes linear ubiquitination of NEMO and IRF7. Consequently, LUBAC is required for LMP1 signaling to full activation of NFκB, but inhibits LMP1-stimulated IRF7 transcriptional activity...
November 30, 2016: 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
#2
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...
November 28, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27892465/distinct-role-of-il-1%C3%AE-in-instigating-disease-in-sharpin-cpdm-mice
#3
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-linear-ubiquitin-chain-assembly-complex-lubac
#4
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...
November 23, 2016: 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
#5
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
#6
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
#7
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
#8
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 IKK kinase 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...
October 24, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27686184/otulin-deficiency-causes-auto-inflammatory-syndrome
#9
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.
September 30, 2016: Cell Research
https://www.readbyqxmd.com/read/27669734/regulation-of-linear-ubiquitin-chain-assembly-complex-by-caspase-mediated-cleavage-of-rnf31
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/27523608/the-deubiquitinase-otulin-is-an-essential-negative-regulator-of-inflammation-and-autoimmunity
#14
Rune Busk Damgaard, Jennifer A Walker, Paola Marco-Casanova, Neil V Morgan, Hannah L Titheradge, Paul R Elliott, Duncan McHale, Eamonn R Maher, Andrew N J McKenzie, David Komander
Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS)...
August 25, 2016: Cell
https://www.readbyqxmd.com/read/27458237/spata2-promotes-cyld-activity-and-regulates-tnf-induced-nf-%C3%AE%C2%BAb-signaling-and-cell-death
#15
Lisa Schlicher, Manuela Wissler, Florian Preiss, Prisca Brauns-Schubert, Celia Jakob, Veronica Dumit, Christoph Borner, Joern Dengjel, Ulrich Maurer
K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely understood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimulation...
October 2016: EMBO Reports
https://www.readbyqxmd.com/read/27348524/hepatitis-b-virus-induced-parkin-dependent-recruitment-of-linear-ubiquitin-assembly-complex-lubac-to-mitochondria-and-attenuation-of-innate-immunity
#16
Mohsin Khan, Gulam Hussain Syed, Seong-Jun Kim, Aleem Siddiqui
Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis...
June 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27291695/review-towards-the-agroecological-management-of-ruminants-pigs-and-poultry-through-the-development-of-sustainable-breeding-programmes-ii-breeding-strategies
#17
F Phocas, C Belloc, J Bidanel, L Delaby, J Y Dourmad, B Dumont, P Ezanno, L Fortun-Lamothe, G Foucras, B Frappat, E González-García, D Hazard, C Larzul, S Lubac, S Mignon-Grasteau, C R Moreno, M Tixier-Boichard, M Brochard
Agroecology uses ecological processes and local resources rather than chemical inputs to develop productive and resilient livestock and crop production systems. In this context, breeding innovations are necessary to obtain animals that are both productive and adapted to a broad range of local contexts and diversity of systems. Breeding strategies to promote agroecological systems are similar for different animal species. However, current practices differ regarding the breeding of ruminants, pigs and poultry...
June 13, 2016: Animal: An International Journal of Animal Bioscience
https://www.readbyqxmd.com/read/27178468/ubiquitination-of-the-transcription-factor-irf-3-activates-ripa-the-apoptotic-pathway-that-protects-mice-from-viral-pathogenesis
#18
Saurabh Chattopadhyay, Teodora Kuzmanovic, Ying Zhang, Jaime L Wetzel, Ganes C Sen
The transcription factor IRF-3 mediates cellular antiviral response by inducing the expression of interferon and other antiviral proteins. In RNA-virus infected cells, IRF-3's transcriptional activation is triggered primarily by RIG-I-like receptors (RLR), which can also activate the RLR-induced IRF-3-mediated pathway of apoptosis (RIPA). Here, we have reported that the pathway of IRF-3 activation in RIPA was independent of and distinct from the known pathway of transcriptional activation of IRF-3. It required linear polyubiquitination of two specific lysine residues of IRF-3 by LUBAC, the linear polyubiquitinating enzyme complex, which bound IRF-3 in signal-dependent fashion...
May 17, 2016: Immunity
https://www.readbyqxmd.com/read/27170506/review-towards-the-agroecological-management-of-ruminants-pigs-and-poultry-through-the-development-of-sustainable-breeding-programmes-i-selection-goals-and-criteria
#19
F Phocas, C Belloc, J Bidanel, L Delaby, J Y Dourmad, B Dumont, P Ezanno, L Fortun-Lamothe, G Foucras, B Frappat, E González-García, D Hazard, C Larzul, S Lubac, S Mignon-Grasteau, C R Moreno, M Tixier-Boichard, M Brochard
Agroecology uses natural processes and local resources rather than chemical inputs to ensure production while limiting the environmental footprint of livestock and crop production systems. Selecting to achieve a maximization of target production criteria has long proved detrimental to fitness traits. However, since the 1990s, developments in animal breeding have also focussed on animal robustness by balancing production and functional traits within overall breeding goals. We discuss here how an agroecological perspective should further shift breeding goals towards functional traits rather than production traits...
May 12, 2016: Animal: An International Journal of Animal Bioscience
https://www.readbyqxmd.com/read/27070702/targeting-non-proteolytic-protein-ubiquitination-for-the-treatment-of-diffuse-large-b-cell-lymphoma
#20
COMPARATIVE STUDY
Yibin Yang, Priscilla Kelly, Arthur L Shaffer, Roland Schmitz, Hee Min Yoo, Xinyue Liu, Da Wei Huang, Daniel Webster, Ryan M Young, Masao Nakagawa, Michele Ceribelli, George W Wright, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Wing C Chan, Elaine S Jaffe, Randy D Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M Staudt
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation...
April 11, 2016: Cancer Cell
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