المؤلفون: Yaming Zhang, Franklin L. Zhong, Chenrui Xu, Zhao Zhi Boo, Kim S. Robinson, Bruno Reversade, Daniel Eng Thiam Teo, Kenneth Lay, Jiawen Zhang, Graham D. Wright, John Soon Yew Lim, Eddie Yong Jun Tan, Kelvin Han Chung Chong, Wah Ing Goh, Qin Gong, Phuong Thao Huynh, Bin Wu

المساهمون: ACS - Heart failure & arrhythmias, Reversade, Bruno, Gong, Q., Robinson, K., Xu, C., Huynh, P.T., Chong, K.H.C., Tan, E.Y.J., Zhang, J., Boo, Z.Z., Teo, D.E.T., Lay, K., Zhang, Y., Lim, J.S.Y., Goh, W.I., Wright, G., Zhong, F.L., Wu, B., School of Medicine

المصدر: Nature communications, 12(1):188. Nature Publishing Group
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)

مصطلحات موضوعية: 0301 basic medicine, Cell biology, Inflammasomes, Biochemistry, Science, General Physics and Astronomy, NLR Proteins, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Inflammasome, Protein filament, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Receptor, Adaptor Proteins, Signal Transducing, Inflammation, Mutation, Multidisciplinary, Chemistry, HEK 293 cells, Caspase 1, Cryoelectron Microscopy, Signal transducing adaptor protein, General Chemistry, Neoplasm Proteins, CARD Signaling Adaptor Proteins, Molecular Docking Simulation, 030104 developmental biology, HEK293 Cells, Cryoelectron microscopy, Signal transduction, Apoptosis Regulatory Proteins, Inflammasome complex, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction

الوصف: Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.
NLRP1 and CARD8 are two recently described sensor proteins for the human inflammasome complex. Here, the authors present the cryo-EM CARD filament structures of the NLRP1 and CARD8 activating domains, which reveal how NLRP1 and CARD8 discriminate between ASC and pro-caspase-1. They further propose a two-step model for NLRP1 activation.

وصف الملف: pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::971fea044a57af53224281deaea2a5a9Test
https://pure.amc.nl/en/publications/structural-basis-for-distinct-inflammasome-complex-assembly-by-human-nlrp1-and-card8Test(f93492eb-c2e0-49e8-a33d-9316ae5981a5).html

المؤلفون: Joanne Wei Kay, Ku, Supatra Tharinee, Marsh, Mui Hoon, Nai, Kim Samirah, Robinson, Daniel Eng Thiam, Teo, Franklin Lei, Zhong, Katherine A, Brown, Thiam Chye, Lim, Chwee Teck, Lim, Yunn-Hwen, Gan

المصدر: Emerging Microbes & Infections
article-version (VoR) Version of Record

مصطلحات موضوعية: Keratinocytes, skin, Burkholderia pseudomallei, integumentary system, Burkholderia, Inflammasomes, keratinocyte, Models, Biological, Melioidosis, inflammasome, Humans, Wounds and Injuries, Epidermis, Cells, Cultured, Research Article

الوصف: Melioidosis is a serious infectious disease endemic in Southeast Asia, Northern Australia and has been increasingly reported in other tropical and subtropical regions in the world. Percutaneous inoculation through cuts and wounds on the skin is one of the major modes of natural transmission. Despite cuts in skin being a major route of entry, very little is known about how the causative bacterium Burkholderia pseudomallei initiates an infection at the skin and the disease manifestation at the skin known as cutaneous melioidosis. One key issue is the lack of suitable and relevant infection models. Employing an in vitro 2D keratinocyte cell culture, a 3D skin equivalent fibroblast-keratinocyte co-culture and ex vivo organ culture from human skin, we developed infection models utilizing surrogate model organism Burkholderia thailandensis to investigate Burkholderia-skin interactions. Collectively, these models show that the bacterial infection was largely limited at the wound’s edge. Infection impedes wound closure, triggers inflammasome activation and cellular extrusion in the keratinocytes as a potential way to control bacterial infectious load at the skin. However, extensive infection over time could result in the epidermal layer being sloughed off, potentially contributing to formation of skin lesions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::18b676f0f3004dcf9b215e5a89f60bc9Test
https://pubmed.ncbi.nlm.nih.gov/34821529Test

المؤلفون: Franklin L. Zhong, Bruno Reversade, Daniel Eng Thiam Teo, Yibo Jin, Qin Gong, Jiawen Zhang, Zhan Yin, Bin Wu, Zongli Li, Yaming Zhang, Zhao Zhi Boo, Renliang Yang, Long Ziqi, Shashi Bhushan

المساهمون: Center for Reproductive Medicine, ACS - Diabetes & metabolism, ARD - Amsterdam Reproduction and Development, ACS - Heart failure & arrhythmias, Reversade, Bruno, Gong, Qin, Long, Ziqi, Zhong, Franklin L., Teo, Daniel Eng Thiam, Jin, Yibo, Yin, Zhan, Boo, Zhao Zhi, Zhang, Yaming, Zhang, Jiawen, Yang, Renliang, Bhushan, Shashi, Li, Zongli, Wu, Bin, School of Medicine, Department of Histology and Embryology, School of Biological Sciences, Institute of Structural Biology

المصدر: Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018)
Nature communications, 9(1):4993. Nature Publishing Group
Nature Communications

مصطلحات موضوعية: Models, Molecular, 0301 basic medicine, Science, Protein domain, General Physics and Astronomy, Mutagenesis (molecular biology technique), Plasma protein binding, Article, General Biochemistry, Genetics and Molecular Biology, RIPK2, Structure-Activity Relationship, 03 medical and health sciences, Protein Domains, Receptor-Interacting Protein Serine-Threonine Kinase 2, NOD1, Humans, Amino Acid Sequence, lcsh:Science, Science and technology, Receptor-interacting protein-2, Helical reconstruction, Kinase-activity, Crohns-disease, Cell-death, Innate, Inflammasome, Domain, ASC, Multidisciplinary, Chemistry, Cryoelectron Microscopy, HEK 293 cells, Signal transducing adaptor protein, General Chemistry, Recombinant Proteins, Science::Biological sciences [DRNTU], Cell biology, CARD Signaling Adaptor Proteins, body regions, HEK293 Cells, 030104 developmental biology, lcsh:Q, Protein Multimerization, Signal transduction, Protein Binding, Signal Transduction

الوصف: Signals arising from bacterial infections are detected by pathogen recognition receptors (PRRs) and are transduced by specialized adapter proteins in mammalian cells. The Receptor-interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) is such an adapter protein that is critical for signal propagation of the Nucleotide-binding-oligomerization-domain-containing proteins 1/2 (NOD1 and NOD2). Dysregulation of this signaling pathway leads to defects in bacterial detection and in some cases autoimmune diseases. Here, we show that the Caspase-activation-and-recruitment-domain (CARD) of RIP2 (RIP2-CARD) forms oligomeric structures upon stimulation by either NOD1-CARD or NOD2-2CARD. We reconstitute this complex, termed the RIPosome in vitro and solve the cryo-EM filament structure of the active RIP2-CARD complex at 4.1 Å resolution. The structure suggests potential mechanisms by which CARD domains from NOD1 and NOD2 initiate the oligomerization process of RIP2-CARD. Together with structure guided mutagenesis experiments at the CARD-CARD interfaces, we demonstrate molecular mechanisms how RIP2 is activated and self-propagating such signal.
The pathogen recognition receptors NOD1/2 recognize bacterial cell wall components and signal through their downstream adapter kinase RIP2 via a CARD (Caspase activation and recruitment domain) mediated oligomerization process. Here the authors present the cryo-EM structure of the active RIP2-CARD filament and discuss implications for NOD1/2-RIP2 signalling.

وصف الملف: pdf; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd24949892b6b033045e393783224eb9Test
http://link.springer.com/article/10.1038/s41467-018-07447-9Test

المؤلفون: Vincent T. K. Chow, Gee Ann Toh, De Yun Wang, Bijin Veonice Au, Justin Jang Hann Chu, Chrissie Lim, Bruno Reversade, Tian Sheng Lew, Daniel Eng Thiam Teo, Hsiao Hui Ong, Kim S. Robinson, Kenneth Lay, Kai Sen Tan, Franklin L. Zhong

المساهمون: ACS - Heart failure & arrhythmias

المصدر: Science, 370(6521):eaay2002. American Association for the Advancement of Science

مصطلحات موضوعية: Multidisciplinary, Immune system, Innate immune system, Immunity, Chemistry, NLRP1, HEK 293 cells, medicine, Signal transducing adaptor protein, Inflammasome, Secretion, medicine.drug, Cell biology

الوصف: A ligand is located, at long last! Members of the Nod-like receptor (NLR) family act as intracellular sensors of infection. Once they recognize pathogen-associated molecular patterns, they assemble into signaling complexes called inflammasomes, which induce proinflammatory cytokines and pyroptotic cell death. Although rodent NLR family pyrin domain containing 1 (NLRP1) can recognize bacterial toxins and protozoan pathogens, the ligands for human NLRP1 have remained elusive. Robinson et al. found that human NLRP1 senses and is activated by enteroviruses. During human rhinovirus (HRV) infection, the HRV 3C protease cleaves an autoinhibitory N-terminal fragment from NLRP1, which is subsequently degraded. The NLRP1 C-terminal fragment that is released then initiates inflammasome formation. This work offers insights into immune sensing of respiratory viral infections and provides an example of the N-terminal glycine degron pathway in human innate immunity. Science , this issue p. eaay2002

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::79f5b80bbf5b1f17f30313173eb81257Test
https://pure.amc.nl/en/publications/enteroviral-3c-protease-activates-the-human-nlrp1-inflammasome-in-airway-epitheliaTest(1746fd11-3a9c-4dd4-9eb2-adaf33736a0d).html

المؤلفون: Kim S. Robinson, John Soon Yew Lim, Franklin L. Zhong, Chenrui Xu, Bin Wu, Bruno Reversade, Daniel Eng Thiam Teo, Jiawen Zhang, Qin Gong, Graham D. Wright, Wah Ing Goh, Yaming Zhang, Zhao Zhi Boo

مصطلحات موضوعية: Protein filament, Programmed cell death, Chemistry, NLRP1, medicine, CARD domain, Inflammasome, Receptor, Inflammasome complex, medicine.drug, NLR Proteins, Cell biology

الوصف: Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIINDUPA rings. Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIINDUPA, which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c4fe4bb4cd9fbbcea40bf985e8835d4eTest
https://doi.org/10.1101/2020.06.17.156307Test

المؤلفون: Andrea D'Osualdo, Cassandra R. Harapas, John E. Connolly, Veonice Bijin Au, Bruno Reversade, Daniel Eng Thiam Teo, Chrissie Lim, Kim S. Robinson, Franklin L. Zhong, Richard Hopkins, Kiat-Yi Tan, William Haowei Xie, Chien-Hsiung Yu, Seth L. Masters, Radoslaw M. Sobota, John C. Reed

المساهمون: Center for Reproductive Medicine, ACS - Diabetes & metabolism, ARD - Amsterdam Reproduction and Development, ACS - Heart failure & arrhythmias

المصدر: Journal of biological chemistry, 293(49), 18864-18878. American Society for Biochemistry and Molecular Biology Inc.

مصطلحات موضوعية: 0301 basic medicine, Inflammasomes, Immunology, Caspase 1, Regulator, Mutation, Missense, NLR Proteins, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, medicine, Humans, Secretion, Enzyme Inhibitors, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Molecular Biology, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, Inflammation, Mutation, HEK 293 cells, Pyroptosis, Signal transducing adaptor protein, Inflammasome, Cell Biology, Dipeptides, Boronic Acids, Cell biology, Neoplasm Proteins, CARD Signaling Adaptor Proteins, 030104 developmental biology, HEK293 Cells, 030220 oncology & carcinogenesis, Apoptosis Regulatory Proteins, medicine.drug, Protein Binding

الوصف: The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1β. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its catalytic activity act synergistically to maintain NLRP1 in its inactive state and repress downstream inflammasome activation. We further identified a single patient-derived germline missense mutation in the NLRP1 FIIND domain that abrogates DPP9 binding, leading to inflammasome hyperactivation seen in the Mendelian autoinflammatory disease Autoinflammation with Arthritis and Dyskeratosis. These results unite recent findings on the regulation of murine Nlrp1b by Dpp8/9 and uncover a new regulatory mechanism for the NLRP1 inflammasome in primary human cells. Our results further suggest that DPP9 could be a multifunctional inflammasome regulator involved in human autoinflammatory diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ebced1164660286b1d64933235a45569Test
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85058148696&origin=inwardTest