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JOURNAL ARTICLE
Chenchen Wang, Chunying Gu, Ying Lv, Hongyu Liu, Yanan Wang, Yongmei Zuo, Guangyu Jiang, Lili Liu, Jiafu Liu
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ligase complex in which the ubiquitin-like (UBL) domains of SHARPIN and HOIL-1L interact with HOIP to determine the structural stability of LUBAC. The interactions between subunits within LUBAC have been a topic of extensive research. However, the impact of the LTM motif on the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP remains unclear. Here, we discover that the absence of the LTM motif in the AlphaFold2-predicted LUBAC structure alters the HOIP-UBA structure...
April 24, 2024: Acta Biochimica et Biophysica Sinica
#2
JOURNAL ARTICLE
Yukiko Takeda, Masahiro Ueki, Junpei Matsuhiro, Erik Walinda, Takayuki Tanaka, Masafumi Yamada, Hiroaki Fujita, Shunichiro Takezaki, Ichiro Kobayashi, Sakura Tamaki, Sanae Nagata, Noriko Miyake, Naomichi Matsumoto, Mitsujiro Osawa, Takahiro Yasumi, Toshio Heike, Fumiaki Ohtake, Megumu K Saito, Junya Toguchida, Junko Takita, Tadashi Ariga, Kazuhiro Iwai
OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS...
June 3, 2024: Journal of Experimental Medicine
#3
JOURNAL ARTICLE
Sophia Davidson, Yuri Shibata, Sophie Collard, Hongyu Zheng, Klara Kong, June M Sun, Pawat Laohamonthonkul, Anthony Cerra, Tobias Kratina, Margaret W Y Li, Carolyn Russell, Anna van Beek, Edwin P Kirk, Rebecca Walsh, Jubran Alqanatish, Abdullah Almojali, Wafaa Alsuwairi, Abdulrahman Alrasheed, Najoua Lalaoui, Paul E Gray, David Komander, Seth L Masters
OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells...
June 3, 2024: Journal of Experimental Medicine
#4
Deion Cheng, Junji Zhu, GuanQun Liu, Michaela U Gack, Donna A MacDuff
The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust antiviral immune response. We have shown previously that HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex (LUBAC), is essential for interferon (IFN) induction in response to viruses sensed by MDA5, but not for viruses sensed by RIG-I. LUBAC contains two unusual E3 ubiquitin ligases, HOIL1 and HOIP. HOIP generates methionine-1-linked polyubiquitin chains, whereas HOIL1 has recently been shown to conjugate ubiquitin onto serine and threonine residues...
April 3, 2024: bioRxiv
#5
JOURNAL ARTICLE
Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Eva Rieser, Önay Veli, Öykü Kaya, Charles Rauch, Shuichiro Nakabo, Hye Sun Kuehn, Mariël Swart, Yanli Wang, Nisa Ilgim Çelik, Anne Molitor, Vahid Ziaee, Nasim Movahedi, Mohammad Shahrooei, Nima Parvaneh, Nasrin Alipour-Olyei, Raphael Carapito, Qin Xu, Silvia Preite, David B Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K Ombrello, Patrycja Hoffmann, Tina Romeo, Natalie T Deuitch, Brynja Matthíasardóttir, James Mullikin, Hirsh Komarow, Jennifer Stoddard, Julie Niemela, Kerry Dobbs, Colin L Sweeney, Holly Anderton, Kate E Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J Kaplan, Junya Toguchida, Christian T Mayer, Sergio D Rosenzweig, Luigi D Notarangelo, Kazuhiro Iwai, John Silke, Pamela L Schwartzberg, Bertrand Boisson, Jean-Laurent Casanova, Seiamak Bahram, Anand Prahalad Rao, Nieves Peltzer, Henning Walczak, Najoua Lalaoui, Ivona Aksentijevich, Daniel L Kastner
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members...
April 12, 2024: Nature Immunology
#6
JOURNAL ARTICLE
Sharmistha Mitra, Baozhi Chen, John M Shelton, Silvia Nitschke, Jun Wu, Lindsay Covington, Mathew Dear, Tori Lynn, Mayank Verma, Felix Nitschke, Yasuhiro Fuseya, Kazuhiro Iwai, Bret M Evers, Berge A Minassian
At least five enzymes including three E3 ubiquitin ligases are dedicated to glycogen's spherical structure. Absence of any reverts glycogen to a structure resembling amylopectin of the plant kingdom. This amylopectinosis (polyglucosan body formation) causes fatal neurological diseases including adult polyglucosan body disease (APBD) due to glycogen branching enzyme deficiency, Lafora disease (LD) due to deficiencies of the laforin glycogen phosphatase or the malin E3 ubiquitin ligase and type 1 polyglucosan body myopathy (PGBM1) due to RBCK1 E3 ubiquitin ligase deficiency...
February 27, 2024: Acta Neuropathologica
#7
REVIEW
Yue Xu, Feng Lin, Guolei Liao, Jiaxing Sun, Wenli Chen, Lei Zhang
Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation...
February 13, 2024: Molecular Neurobiology
#8
JOURNAL ARTICLE
Yasuhiro Fuseya, Keiichiro Kadoba, Xiaoxi Liu, Hiroyuki Suetsugu, Takeshi Iwasaki, Koichiro Ohmura, Takayuki Sumida, Yuta Kochi, Akio Morinobu, Chikashi Terao, Kazuhiro Iwai
Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP...
February 8, 2024: JCI Insight
#9
JOURNAL ARTICLE
Ying Jin, Yazhi Peng, Jie Xu, Ye Yuan, Nan Yang, Zemei Zhang, Lei Xu, Lin Li, Yulian Xiong, Dejiao Sun, Yamu Pan, Ruiqing Wu, Jian Fu
Hypoxia-inducible factor 1 (HIF1) is critically important for driving angiogenesis and tumorigenesis. Linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase capable of catalyzing protein linear ubiquitination to date, is implicated in cell signaling and associated with cancers. However, the role and mechanism of LUBAC in regulating the expression and function of HIF1α, the labile subunit of HIF1, remain to be elucidated. Herein we showed that LUBAC increases HIF1α protein expression in cultured cells and tissues of human lung cancer and enhances HIF1α DNA-binding and transcriptional activities, which are dependent upon LUBAC enzymatic activity...
January 25, 2024: Oncogenesis
#10
JOURNAL ARTICLE
Nadine Weinelt, Kaja Nicole Wächtershäuser, Gulustan Celik, Birte Jeiler, Isabelle Gollin, Laura Zein, Sonja Smith, Geoffroy Andrieux, Tonmoy Das, Jens Roedig, Leonard Feist, Björn Rotter, Melanie Boerries, Francesco Pampaloni, Sjoerd J L van Wijk
Plasma membrane accumulation of phosphorylated mixed lineage kinase domain-like (MLKL) is a hallmark of necroptosis, leading to membrane rupture and inflammatory cell death. Pro-death functions of MLKL are tightly controlled by several checkpoints, including phosphorylation. Endo- and exocytosis limit MLKL membrane accumulation and counteract necroptosis, but the exact mechanisms remain poorly understood. Here, we identify linear ubiquitin chain assembly complex (LUBAC)-mediated M1 poly-ubiquitination (poly-Ub) as novel checkpoint for necroptosis regulation downstream of activated MLKL in cells of human origin...
January 20, 2024: Cell Death & Disease
#11
JOURNAL ARTICLE
Zehang Zheng, Xingru Shang, Kai Sun, Yanjun Hou, Xiong Zhang, Jingting Xu, Haigang Liu, Zhaoxuan Ruan, Liangcai Hou, Zhou Guo, Genchun Wang, Fei Xu, Fengjing Guo
Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes...
January 2, 2024: Free Radical Biology & Medicine
#12
JOURNAL ARTICLE
Kouki Hoshino, Seshiru Nakazawa, Takehiko Yokobori, Kei Hagiwara, Norihiro Ishii, Mariko Tsukagoshi, Takamichi Igarashi, Kenichiro Araki, Norifumi Harimoto, Fuminori Tokunaga, Ken Shirabe
RNF31 is a multifunctional RING finger protein implicated in various inflammatory diseases and cancers. It functions as a core component of the linear ubiquitin chain assembly complex (LUBAC), which activates the nuclear factor kappaB (NF-κB) pathway via the generation of the Met1-linked linear ubiquitin chain. We aimed to clarify the role of RNF31 in the pathogenesis of hepatocellular carcinoma (HCC) and its relevance as a therapeutic target. High RNF31 expression in HCC, assessed by both immunohistochemistry and mRNA levels, was related to worse survival rates among patients with HCC...
January 3, 2024: Scientific Reports
#13
REVIEW
Jack Li, Sijin Liu, Shitao Li
Linear ubiquitination is a distinct type of ubiquitination that involves attaching a head-to-tail polyubiquitin chain to a substrate protein. Early studies found that linear ubiquitin chains are essential for the TNFα- and IL-1-mediated NF-κB signaling pathways. However, recent studies have discovered at least sixteen linear ubiquitination substrates, which exhibit a broader activity than expected and mediate many other signaling pathways beyond NF-κB signaling. Dysregulation of linear ubiquitination in these pathways has been linked to many types of cancers, such as lymphoma, liver cancer, and breast cancer...
November 28, 2023: Cell Communication and Signaling: CCS
#14
JOURNAL ARTICLE
Helena C Teague, Charlotte Lefevre, Eva Rieser, Lina Wolfram, Diego de Miguel, Daniel Patricio de Oliveira, Marisa Oliveira, Daniel S Mansur, Nerea Irigoyen, Henning Walczak, Brian J Ferguson
The ability of cells to mount an interferon response to virus infections depends on intracellular nucleic acid sensing pattern recognition receptors (PRRs). RIG-I is an intracellular PRR that binds short double-stranded viral RNAs to trigger MAVS-dependent signalling. The RIG-I/MAVS signalling complex requires the coordinated activity of multiple kinases and E3 ubiquitin ligases to activate the transcription factors that drive type I and type III interferon production from infected cells. The linear ubiquitin chain assembly complex (LUBAC) regulates the activity of multiple receptor signalling pathways in both ligase-dependent and -independent ways...
January 2024: Cell Death and Differentiation
#15
JOURNAL ARTICLE
Yan Zhang, Xiaolong Xu, Yaru Wang, Yingli Wang, Xindi Zhou, Lifeng Pan
HOIL-1L and SHARPIN are two essential regulatory subunits of the linear ubiquitin chain assembly complex (LUBAC), which is the only known E3 ligase complex generating linear ubiquitin chains. In addition to their LUBAC-dependent functions, HOIL-1L and SHARPIN alone play crucial roles in many LUBAC-independent cellular processes. Importantly, deficiency of HOIL-1L or SHARPIN leads to severe disorders in humans or mice. However, the mechanistic bases underlying the multi-functions of HOIL-1L and SHARPIN are still largely unknown...
November 11, 2023: Biochemical and Biophysical Research Communications
#16
REVIEW
Yuxuan Li, Jie Zhu, Zongdong Yu, Fengguang Zhai, Hong Li, Xiaofeng Jin
Apoptosis is a programmed cell death process critical to cell development and tissue homeostasis in multicellular organisms. Defective apoptosis is a crucial step in the malignant transformation of cells, including hepatocellular carcinoma (HCC), where the apoptosis rate is higher than in normal liver tissues. Ubiquitination, a post-translational modification process, plays a precise role in regulating the formation and function of different death-signaling complexes, including those involved in apoptosis. Aberrant expression of E3 ubiquitin ligases (E3s) in liver cancer (LC), such as cellular inhibitors of apoptosis proteins (cIAPs), X chromosome-linked IAP (XIAP), and linear ubiquitin chain assembly complex (LUBAC), can contribute to HCC development by promoting cell survival and inhibiting apoptosis...
2023: American Journal of Cancer Research
#17
Jayashree Kadirvelu, Savannah E Jacobs, Ruochuan Liu, Antoinette J Charles, Jun Yin, Angela M Mabb
Of the hundreds of E3 ligases found in the human genome, the RING-between RING (RBR) E3 ligase in the LUBAC (linear ubiquitin chain assembly complex) complex HOIP (HOIL-1-interacting protein or RNF31), contains a unique domain called LDD (linear ubiquitin chain determining domain). HOIP is the only E3 ligase known to form linear ubiquitin chains, which regulate inflammatory responses and cell death via activation of the NF-κB pathway. We identified an amino acid sequence within the RNF216 E3 ligase that shares homology to the LDD domain found in HOIP (R2-C)...
October 19, 2023: bioRxiv
#18
Tara D Fischer, Eric N Bunker, Peng-Peng Zhu, François Le Guerroué, Eunice Dominguez-Martin, Francesco Scavone, Robert Cohen, Tingting Yao, Yan Wang, Achim Werner, Richard J Youle
STING activation by cyclic dinucleotides in mammals induces interferon- and NFκB -related gene expression, and the lipidation of LC3B at Golgi membranes. While mechanisms of the interferon response are well understood, the mechanisms of NFκB activation mediated by STING remain unclear. We report that STING activation induces K63- and M1-linked/linear ubiquitin chain formation at LC3B-associated Golgi membranes. Loss of the LUBAC E3 ubiquitin ligase prevents formation of linear, but not K63-linked ubiquitin chains or STING activation and inhibits STING-induced NFκB and IRF3-mediated signaling in monocytic THP1 cells...
October 16, 2023: bioRxiv
#19
JOURNAL ARTICLE
Peng Chen, Zheyu Dong, Wei Zhu, Junling Chen, Yuxin Zhou, Qiuyue Ye, Xinxin Liao, Yongfa Tan, Chuanjiang Li, Yuhao Wang, Huajin Pang, Chunhua Wen, Yuchuan Jiang, Xiaoqing Li, Bo Li, Aihetaimu Aimaier, Li Lin, Jian Sun, Jiajie Hou, Libo Tang, Jinlin Hou, Yongyin Li
BACKGROUND AIMS: Cancer stem cells (CSCs) contribute to therapy resistance in hepatocellular carcinoma (HCC). Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs. METHODS: The effect of LUBAC on sorafenib response was evaluated...
October 11, 2023: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
#20
REVIEW
Liyuan Gao, Wei Zhang, Xiao Hui Shi, Xiaoyan Chang, Yi Han, Chundi Liu, Zhitao Jiang, Xiang Yang
Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases...
October 10, 2023: Cell Death & Disease
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