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https://www.readbyqxmd.com/read/28647349/inhibitor-of-apoptosis-proteins-iaps-limit-ripk1-mediated-skin-inflammation
#1
H Anderton, J A Rickard, G A Varigos, N Lalaoui, J Silke
Inhibitor of Apoptosis Proteins (IAPs) are critical regulators of cell death and survival pathways. Mice lacking cellular IAP (cIAP) 1 and either cIAP2 or X-linked IAP (XIAP) die in utero, and myeloid lineage-specific deletion of all IAPs causes sterile inflammation, but their role in the skin is unknown. We generated epidermal-specific IAPs deficient mice and found that combined genetic deletion of cIAP1 in keratinocytes and ubiquitous cIAP2 deletion (cIap1(EKO/EKO).cIap2(-/-)) caused profound skin inflammation and keratinocyte death, lethal by post-partum day 10...
June 21, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28481331/lubac-synthesized-linear-ubiquitin-chains-restrict-cytosol-invading-bacteria-by-activating-autophagy-and-nf-%C3%AE%C2%BAb
#2
Jessica Noad, Alexander von der Malsburg, Claudio Pathe, Martin A Michel, David Komander, Felix Randow
Cell-autonomous immunity relies on the ubiquitin coat surrounding cytosol-invading bacteria functioning as an 'eat-me' signal for xenophagy. The origin, composition and precise mode of action of the ubiquitin coat remain incompletely understood. Here, by studying Salmonella Typhimurium, we show that the E3 ligase LUBAC generates linear (M1-linked) polyubiquitin patches in the ubiquitin coat, which serve as antibacterial and pro-inflammatory signalling platforms. LUBAC is recruited via its subunit HOIP to bacterial surfaces that are no longer shielded by host membranes and are already displaying ubiquitin, suggesting that LUBAC amplifies and refashions the ubiquitin coat...
May 8, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28475177/the-role-of-hybrid-ubiquitin-chains-in-the-myd88-and-other-innate-immune-signalling-pathways
#3
REVIEW
Philip Cohen, Sam Strickson
The adaptor protein MyD88 is required for signal transmission by toll-like receptors and receptors of the interleukin-1 family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex...
May 5, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28475174/diverse-ubiquitin-linkages-regulate-rip-kinases-mediated-inflammatory-and-cell-death-signaling
#4
REVIEW
Axel Witt, Domagoj Vucic
Members of the RIP kinase family are key regulators of inflammation and cell death signaling implicated in maintaining immune responses and proper tissue homeostasis. Increasing evidence points to post-translational modifications of RIP1, RIP2 and RIP3 as being critical for regulating their function. Ubiquitination and the E3 ligases, such as inhibitors of apoptosis (IAP) proteins and LUBAC, that direct substrate selectivity as well as the deubiquitinating enzymes, such as A20 and OTULIN, that reverse these modifications dictate the outcome of RIP kinase signaling...
May 5, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28469620/nf-%C3%AE%C2%BAb-pathway-in-autoinflammatory-diseases-dysregulation-of-protein-modifications-by-ubiquitin-defines-a-new-category-of-autoinflammatory-diseases
#5
REVIEW
Ivona Aksentijevich, Qing Zhou
Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28446710/linear-ubiquitin-chains-enzymes-mechanisms-and-biology
#6
REVIEW
Katrin Rittinger, Fumiyo Ikeda
Ubiquitination is a versatile post-translational modification that regulates a multitude of cellular processes. Its versatility is based on the ability of ubiquitin to form multiple types of polyubiquitin chains, which are recognized by specific ubiquitin receptors to induce the required cellular response. Linear ubiquitin chains are linked through Met 1 and have been established as important players of inflammatory signalling and apoptotic cell death. These chains are generated by a ubiquitin E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) that is thus far the only E3 ligase capable of forming linear ubiquitin chains...
April 2017: Open Biology
https://www.readbyqxmd.com/read/28325627/tlrs-go-linear-on-the-ubiquitin-edge
#7
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
#8
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...
May 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
#9
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...
May 2, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28230260/elevation-of-sharpin-protein-levels-in-prostate-adenocarcinomas-promotes-metastasis-and-impairs-patient-survivals
#10
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
#11
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
#12
Yutaka Shimizu, Nieves Peltzer, Alexandra Sevko, Elodie Lafont, Aida Sarr, Helena Draberova, Henning Walczak
Linear ubiquitination is a key posttranslational modification that regulates immune signaling and cell death pathways, notably tumor necrosis factor receptor 1 (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, of which the catalytic core component is heme-oxidized iron regulatory protein 2 ubiquitin ligase-1-interacting protein (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...
June 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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