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https://www.readbyqxmd.com/read/29897336/frmd8-promotes-inflammatory-and-growth-factor-signalling-by-stabilising-the-irhom-adam17-sheddase-complex
#1
Ulrike Künzel, Adam Graham Grieve, Yao Meng, Boris Sieber, Sally A Cowley, Matthew Freeman
Many intercellular signals are synthesised as transmembrane precursors that are released by proteolytic cleavage ('shedding') from the cell surface. ADAM17, a membrane-tethered metalloprotease, is the primary shedding enzyme responsible for the release of the inflammatory cytokine TNFα and several EGF receptor ligands. ADAM17 exists in complex with the rhomboid-like iRhom proteins, which act as cofactors that regulate ADAM17 substrate shedding. Here we report that the poorly characterised FERM domain-containing protein FRMD8 is a new component of iRhom2/ADAM17 sheddase complex...
June 13, 2018: ELife
https://www.readbyqxmd.com/read/29891514/neutrophil-and-macrophage-cell-surface-csf-1-shed-by-adam17-drives-mouse-macrophage-proliferation-in-acute-and-chronic-inflammation
#2
Jingjing Tang, Jeremy M Frey, Carole L Wilson, Angela Moncada-Pazos, Clémence Levet, Matthew Freeman, Michael E Rosenfeld, E Richard Stanley, Elaine W Raines, Karin E Bornfeldt
Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post monocyte recruitment in inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor-1 (CSF-1) in the peritoneum, and is rescued by intraperitoneal injection of CSF-1...
June 11, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29776906/blood-induced-bone-loss-in-murine-hemophilic-arthropathy-is-prevented-by-blocking-the-irhom2-adam17-tnf%C3%AE-pathway
#3
Coline Haxaire, Narine Hakobyan, Tania Pannellini, Camila Carballo, David McIlwain, Tak W Mak, Scott Rodeo, Suchitra Acharya, Daniel Li, Jackie Szymonifka, Xiangqian Song, Sébastien Monette, Alok Srivastava, Jane E Salmon, Carl P Blobel
Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder Hemophilia A. HA typically begins with hemophilic synovitis (HS) that resembles inflammatory arthritides such as rheumatoid arthritis (RA) and frequently results in bone loss in patients. A major cause of RA is inappropriate release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) by the TNFα convertase (TACE, also referred to as ADAM17) and its regulator, iRhom2...
May 18, 2018: Blood
https://www.readbyqxmd.com/read/29712987/author-correction-role-of-irhom2-in-intestinal-ischemia-reperfusion-mediated-acute-lung-injury
#4
Jee Hyun Kim, Jihye Kim, Jaeyoung Chun, Changhyun Lee, Jong Pil Im, Joo Sung Kim
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
May 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29523849/p63-is-a-key-regulator-of-irhom2-signalling-in-the-keratinocyte-stress-response
#5
Paola Arcidiacono, Catherine M Webb, Matthew A Brooke, Huiqing Zhou, Paul J Delaney, Keat-Eng Ng, Diana C Blaydon, Andrew Tinker, David P Kelsell, Anissa Chikh
Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress-associated signalling pathways in normal and hyperproliferative keratinocytes...
March 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29491382/role-of-irhom2-in-intestinal-ischemia-reperfusion-mediated-acute-lung-injury
#6
Jee Hyun Kim, Jihye Kim, Jaeyoung Chun, Changhyun Lee, Jong Pil Im, Joo Sung Kim
Intestinal ischemia-reperfusion (I/R) may cause acute systemic and lung inflammation. However, the detailed mechanism of this inflammatory cascade has not been fully elucidated. Inactive rhomboid protein 2 (iRhom2) is essential for the maturation of TNF-α converting enzyme (TACE), which is required for TNF-α secretion. We evaluated the role of iRhom2 in a mouse model of intestinal I/R using iRhom2 knockout (KO) and wild-type (WT) mice. Lung injury following intestinal I/R was significantly attenuated in iRhom2 KO mice compared with WT mice...
February 28, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29415889/irhom2-mediated-proinflammatory-signalling-regulates-heart-repair-following-myocardial-infarction
#7
Damien N Barnette, Thomas J Cahill, Mala Gunadasa-Rohling, Carolyn A Carr, Matthew Freeman, Paul R Riley
The role of proinflammation, and specifically TNF-α, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-α, we reveal increased macrophages (MΦs) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 MΦs, respectively...
February 8, 2018: JCI Insight
https://www.readbyqxmd.com/read/29369823/irhom2-promotes-lupus-nephritis-through-tnf-%C3%AE-and-egfr-signaling
#8
Xiaoping Qing, Yurii Chinenov, Patricia Redecha, Michael Madaio, Joris Jth Roelofs, Gregory Farber, Priya D Issuree, Laura Donlin, David R Mcllwain, Tak W Mak, Carl P Blobel, Jane E Salmon
Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney diseases. Here, we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double-stranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and TNF-α signaling in the kidney tissues...
April 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29221422/total-flavones-of-abelmoschus-manihot-improve-diabetic-nephropathy-by-inhibiting-the-irhom2-tace-signalling-pathway-activity-in-rats
#9
Su Liu, Lifang Ye, Jing Tao, Chao Ge, Liji Huang, Jiangyi Yu
CONTEXT: Total flavones extracted from Abelmoschus manihot L. (Malvaceae) medic (TFA) have been proven clinically effective at improving renal inflammation and glomerular injury in chronic kidney disease (CKD). OBJECTIVE: This study evaluated the function of TFA as an inhibitor of iRhom2/TACE (tumour necrosis factor-α converting enzyme) signalling and investigated its anti-DN (diabetic nephropathy) effects in a DN rat model. MATERIALS AND METHODS: In vitro, cells were treated with 200 μg/mL advanced glycation end products (AGEs), and then co-cultured with 20 μg/mL TFA for 24 h...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/29155878/irhom2-is-essential-for-innate-immunity-to-rna-virus-by-antagonizing-er-and-mitochondria-associated-degradation-of-visa
#10
Wei-Wei Luo, Shu Li, Chen Li, Zhou-Qin Zheng, Pan Cao, Zhen Tong, Huan Lian, Su-Yun Wang, Hong-Bing Shu, Yan-Yi Wang
VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms...
November 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29045841/phosphorylation-of-irhom2-controls-stimulated-proteolytic-shedding-by-the-metalloprotease-adam17-tace
#11
Miguel Cavadas, Ioanna Oikonomidi, Catarina J Gaspar, Emma Burbridge, Marina Badenes, Inês Félix, Alfonso Bolado, Tianyi Hu, Andrea Bileck, Christopher Gerner, Pedro M Domingos, Alex von Kriegsheim, Colin Adrain
Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28965953/irhom2-deficiency-relieves-tnf-%C3%AE-associated-hepatic-dyslipidemia-in-long-term-pm2-5-exposed-mice
#12
Chen-Xu Ge, Yu-Ting Qin, De-Shuai Lou, Qiang Li, Yuan-Yuan Li, Zhong-Ming Wang, Wei-Wei Yang, Ming Wang, Nan Liu, Zhen Wang, Peng-Xing Zhang, Yan-Yang Tu, Jun Tan, Min-Xuan Xu
Accumulating researches reported that particulate matter (PM2.5) is a risk factor for developing various diseases, including metabolic syndrome. Recently, inactive rhomboid protein 2 (iRhom2) was considered as a necessary modulator for shedding of tumor necrosis factor-α (TNF-α) in immune cells. TNF-α, a major pro-inflammatory cytokine, was linked to various pathogenesis of diseases, including dyslipidemia. Here, wild type (WT) and iRhom2-knockout (iRhom2-/- ) mice were used to investigate the effects of iRhom2 on PM2...
December 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28815577/emerging-roles-of-rhomboid-like-pseudoproteases-in-inflammatory-and-innate-immune-responses
#13
REVIEW
Wei-Wei Luo, Hong-Bing Shu
Rhomboid-like pseudoproteases are a conserved superfamily of proteins related to the rhomboid intramembrane serine proteases that lack key catalytic residues. iRhom2, a member of the rhomboid-like pseudoprotease superfamily, regulates the maturation and trafficking of ADAM17 and is associated with inflammatory arthritis. Recent studies demonstrate that iRhom2 is also involved in innate immunity by regulating the trafficking and stability of MITA (also called STING), which is a central adaptor in innate antiviral signalling pathways...
October 2017: FEBS Letters
https://www.readbyqxmd.com/read/28703301/the-xenoestrogens-biphenol-a-and-nonylphenol-differentially-regulate-metalloprotease-mediated-shedding-of-egfr-ligands
#14
Paulina Urriola-Muñoz, Xue Li, Thorsten Maretzky, David R McIlwain, Tak W Mak, Juan G Reyes, Carl P Blobel, Ricardo D Moreno
The xenoestrogens bisphenol-A (BPA) and nonylphenol (NP) are endocrine disruptors used in the plastic polymer industry to manufacture different products for human use. Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor α (TNF-α). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR-ligands. We report that BPA and NP can stimulate the release of the ADAM17-substrates HB-EGF and TGF-α...
March 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28432785/phosphorylation-of-irhom2-at-the-plasma-membrane-controls-mammalian-tace-dependent-inflammatory-and-growth-factor-signalling
#15
Adam Graham Grieve, Hongmei Xu, Ulrike Künzel, Paul Bambrough, Boris Sieber, Matthew Freeman
Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor receptor. iRhoms, catalytically inactive members of the rhomboid-like superfamily, have been shown to control the ER-to-Golgi transport and maturation of TACE. Here, we reveal that iRhom2 remains associated with TACE throughout the secretory pathway, and is stabilised at the cell surface by this interaction...
April 22, 2017: ELife
https://www.readbyqxmd.com/read/28132838/human-cytomegalovirus-tegument-protein-ul82-inhibits-sting-mediated-signaling-to-evade-antiviral-immunity
#16
Yu-Zhi Fu, Shan Su, Yi-Qun Gao, Pei-Pei Wang, Zhe-Fu Huang, Ming-Ming Hu, Wei-Wei Luo, Shu Li, Min-Hua Luo, Yan-Yi Wang, Hong-Bing Shu
Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex...
February 8, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28128203/rhomboid-family-member-2-regulates-cytoskeletal-stress-associated-keratin-16
#17
Thiviyani Maruthappu, Anissa Chikh, Benjamin Fell, Paul J Delaney, Matthew A Brooke, Clemence Levet, Angela Moncada-Pazos, Akemi Ishida-Yamamoto, Diana Blaydon, Ahmad Waseem, Irene M Leigh, Matthew Freeman, David P Kelsell
Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2(-/-) mice compared with irhom2(+/+)mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6...
January 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28104813/structural-modeling-defines-transmembrane-residues-in-adam17-that-are-crucial-for-rhbdf2-adam17-dependent-proteolysis
#18
Xue Li, Thorsten Maretzky, Jose Manuel Perez-Aguilar, Sébastien Monette, Gisela Weskamp, Sylvain Le Gall, Bruce Beutler, Harel Weinstein, Carl P Blobel
A disintegrin and metalloproteinase 17 (ADAM17) controls the release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα, also known as TNF) and is crucial for protecting the skin and intestinal barrier by proteolytic activation of epidermal growth factor receptor (EGFR) ligands. The seven-membrane-spanning protein called inactive rhomboid 2 (Rhbdf2; also known as iRhom2) is required for ADAM17-dependent TNFα shedding and crosstalk with the EGFR, and a point mutation (known as sinecure, sin) in the first transmembrane domain (TMD) of Rhbdf2 (Rhbdf2(sin)) blocks TNFα shedding, yet little is known about the underlying mechanism...
March 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28033581/irhom2-is-involved-in-lipopolysaccharide-induced-cardiac-injury-in-vivo-and-in-vitro-through-regulating-inflammation-response
#19
Xue-Li Lu, Cui-Hua Zhao, Han Zhang, Xin-Liang Yao
Heart is a complex assembly of many cell types constituting of myocardium, endocardium and epicardium that intensively communicate to each other in order to maintain the proper cardiac function. Previous research has demonstrated that lipopolysaccharide (LPS) can induce myocardial dysfunction. iRhom2 is encoded by the gene Rhbdf2, regulating inflammation via tumor necrosis factor-α (TNF-α). In this study, we attempted to investigate the role of iRhom2 in LPS-induced cardiac injury and clarify the potential mechanism...
February 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27601030/irhom2-regulates-csf1r-cell-surface-expression-and-non-steady-state-myelopoiesis-in-mice
#20
Xiaoping Qing, Lindsay Rogers, Arthur Mortha, Yonit Lavin, Patricia Redecha, Priya D Issuree, Thorsten Maretzky, Miriam Merad, David McIlwain, Tak W Mak, Christopher M Overall, Carl P Blobel, Jane E Salmon
CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells...
December 2016: European Journal of Immunology
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