Article
Immunology
Sofiya Pisarenka, Nicole C. Meyer, Xue Xiao, Renee Goodfellow, Carla M. Nester, Yuzhou Zhang, Richard J. H. Smith
Summary: C3 glomerulopathies (C3G) are ultra-rare complement-mediated diseases that lead to end-stage renal disease (ESRD) within 10 years of diagnosis in similar to 50% of patients. The overactivation of the alternative pathway (AP) of complement in the fluid phase and on the surface of the glomerular endothelial glycomatrix is the underlying cause of C3G. This study presents an in vitro model to evaluate the activity of the complement system in C3G using an extracellular matrix substitute.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Immunology
Marie -Sophie Meuleman, Anne Grunenwald, Sophie Chauvet
Summary: C3 glomerulopathy (C3G) is a rare and complex kidney disease that primarily affects young adults. It is driven by uncontrolled overactivation of the alternative complement pathway, mainly of acquired origin. Functional characterization of complement abnormalities identified in patients and experimental models has improved the understanding of the disease, making C3G a prototype of complement-mediated diseases. The contribution of C3 convertase and C5 convertase in disease occurrence, phenotype, and severity is established, offering potential therapeutic interventions based on complement inhibitors.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Urology & Nephrology
Alyssa C. Gilmore, Yuchun Zhang, H. Terence Cook, Deborah P. Lavin, Suresh Katti, Yi Wang, Krista K. Johnson, SungKwon Kim, Matthew C. Pickering
Summary: In this study, the effectiveness of two fusion proteins containing factor H regulatory domains in treating C3 glomerulopathy was assessed. The results showed that both proteins successfully restored circulating alternative pathway activity and reduced glomerular C3 deposition in factor H-deficient mice, indicating a potential therapeutic option for this disease.
KIDNEY INTERNATIONAL
(2021)
Article
Immunology
Wen Q. Qiu, Shaopeiwen Luo, Stefanie A. Ma, Priyanka Saminathan, Herman Li, Jenny M. Gunnersen, Harris A. Gelbard, Jennetta W. Hammond
Summary: The Sez6 family members are novel complement regulators that inhibit C3 convertases with varying degrees of efficacy in the classical and alternative pathways, promoting C3b degradation. Sez6L2, as a representative member, accelerates the dissociation of C3 convertases and functions as a cofactor for Factor I to facilitate C3b cleavage, with no cofactor activity toward C4b.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Alexandra T. T. Matola, Angela Fulop, Bernadette Rojkovich, Gyorgy Nagy, Gabriella Sarmay, Mihaly Jozsi, Barbara Uzonyi
Summary: This study analyzed the presence and role of autoantibodies against complement proteins in Hungarian rheumatoid arthritis (RA) patients. Autoantibodies against C1q, MBL, and FB were detected in a small number of patients and were found to have inhibitory effects on complement function. These results support the involvement of the complement system in the pathomechanism of RA and suggest the presence of protective autoantibodies against the alternative pathway C3 convertase in some patients.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mariann Kremlitzka, Lucie Colineau, Alicja A. Nowacka, Frida C. Mohlin, Katarzyna Wozniak, Anna M. Blom, Ben C. King
Summary: This study demonstrates the presence and origin of intracellular, cytosolic C3, and reveals its functions in intracellular detection of cytoinvasive pathogens.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Urology & Nephrology
Jiwon Ryu, Eunji Baek, Hyung-Eun Son, Ji-Young Ryu, Jong Cheol Jeong, Sejoong Kim, Ki Young Na, Dong-Wan Chae, Seong Pyo Kim, Su Hwan Kim, Jong Hyun Jhee, Tae Ik Chang, Bum Soon Choi, Ho Jun Chin
Summary: This study investigated the pathological and clinical differences between primary glomerulonephritis (GN) cases with dominant C3 deposition (C3D-GN) and non-dominant C3 deposition (C3ND-GN). Results showed that patients with C3D-GN had greater progression of renal injury and higher mortality. These findings contribute to a better understanding of the characteristics and prognosis of C3 dominant GN.
KIDNEY RESEARCH AND CLINICAL PRACTICE
(2023)
Article
Biochemistry & Molecular Biology
Cristina Zanchi, Monica Locatelli, Daniela Corna, Domenico Cerullo, Elane Fishilevich, Dhruv Desai, Daniela Rottoli, Roberta Donadelli, Marina Noris, Carlamaria Zoja, Giuseppe Remuzzi, Ariela Benigni
Summary: Uncontrolled activation of the alternative pathway of complement is a primary cause of C3 glomerulopathy, a rare disease characterized by C3 fragment deposition and glomerular damage. New drugs targeting this dysregulation show promise for treating the disease.
MOLECULAR IMMUNOLOGY
(2023)
Article
Immunology
Sanjaya K. Sahu, Ayfe N. Ozanturk, Devesha H. Kulkarni, Lina Ma, Ruteja A. Barve, Linus Dannull, Angel Lu, Marick Starick, Ja'Nia McPhatter, Lorena Garnica, Maxwell Sanfillipo-Burchman, Jeremy Kunen, Xiaobo Wu, Andrew E. Gelman, Steven L. Brody, John P. Atkinson, Hrishikesh S. Kulkarni
Summary: The source of C3 affects pneumonia and cell survival. Liver-derived C3 protects the lung from injuries, while locally derived C3 and Factor B protect the lung mucosal barrier effectively.
SCIENCE IMMUNOLOGY
(2023)
Article
Immunology
Tilman Schmidt, Sara Afonso, Luce Perie, Karin Heidenreich, Sonia Wulf, Christian F. Krebs, Peter F. Zipfel, Thorsten Wiech
Summary: C3 glomerulopathy is a heterogeneous group of disorders characterized by dominant C3 deposition. The current biopsy-based diagnostic approaches are not sufficient to guide therapy decisions. Therefore, the authors propose an interdisciplinary diagnostic approach, including multiple analysis methods, to help guide therapy for renal diseases with relevant complement activation.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Yingbo Ma, Xueqing Ding, Mingxi Shao, Yichao Qiu, Shengjie Li, Wenjun Cao, Gezhi Xu
Summary: This study investigated the association between serum complement components and AMD. The results showed that higher levels of C1q and lower levels of C3 were associated with increased risk of AMD in female patients. This suggests that the complement classical pathway may be involved in the development of AMD, especially in females.
JOURNAL OF INFLAMMATION RESEARCH
(2022)
Article
Dermatology
William D. Jackson, Alessandro Gulino, Liliane Fossati-Jimack, Rocio Castro Seoane, Kunyuan Tian, Katie Best, Joerg Koehl, Beatrice Belmonte, Jessica Strid, Marina Botto
Summary: Research suggests that the complement system plays a role in cSCC, with C3 driving tumorigenesis during chronic skin inflammation independently of downstream generation of C5a or membrane attack complex.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2021)
Article
Immunology
Xiaoting Wu, Danyu You, Jiong Cui, Liyan Yang, Liyu Lin, Yi Chen, Changsheng Xu, Guili Lian, Jianxin Wan
Summary: C3 plays an important role in inflammation and kidney injury. This study found that ischemia reperfusion injury (IRI) in the kidney leads to increased infiltration of neutrophils and formation of neutrophil extracellular traps (NETs). Inhibiting neutrophil infiltration can reduce kidney injury and inflammation. C3 deficiency can ameliorate acute kidney injury (AKI) by reducing neutrophil infiltration and the formation of NETs.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Marloes A. H. M. Michels, Nicole C. A. J. van de Kar, Sanne A. W. van Kraaij, Sebastian A. Sarlea, Valentina Gracchi, Flore A. P. T. Engels, Eiske M. Dorresteijn, Johannes van der Deure, Caroline Duineveld, Jack F. M. Wetzels, Lambertus P. W. J. van den Heuvel, Elena B. Volokhina
Summary: The study investigated the activity of the classical pathway convertase in patients with C3G and IC-MPGN, revealing prolonged activity in some patients attributed to immunoglobulins and non-immunoglobulin factors. This finding provides new insights into the mechanisms of CP convertase overactivity in C3G/IC-MPGN.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Obstetrics & Gynecology
Phumelele Kikine, Yazira Pillay, Thajasvarie Naicker
Summary: The study found a significant decrease in factor B concentration in the HIV+ group, suggesting HIV may inhibit the alternative pathway to evade immune detection. The results also showed that the alternative pathway is not excessively activated in PE during the third trimester.
HYPERTENSION IN PREGNANCY
(2022)
Article
Immunology
Heidi Gytz Olesen, Iliana Michailidou, Wioleta M. Zelek, Jeroen Vreijling, Patrick Ruizendaal, Ferry de Klein, J. Arnoud Marquart, Thomas B. Kuipers, Hailiang Mei, Yuchun Zhang, Muhammad Ahasan, Krista K. Johnson, Yi Wang, B. Paul Morgan, Marcus van Dijk, Kees Fluiter, Gregers Rom Andersen, Frank Baas
Summary: Damage and disease of nerves activate the complement system, leading to the formation of the membrane attack complex (MAC) and delaying nerve regeneration. By studying the complement component C6, researchers have developed a novel therapeutic monoclonal antibody, CP010, that prevents MAC formation and shows potential therapeutic use in neurological diseases. The antibody blocks the interaction between C6 and C5/C5b and demonstrates efficacy in preventing disease and relapse in animal models.
JOURNAL OF INNATE IMMUNITY
(2023)
Article
Allergy
Melanie Plum, Luna Tjerrild, Tim Raiber, Frank Bantleon, Sara Bantleon, Michaela Miehe, Frederic Jabs, Henning Seismann, Christian Moebs, Wolfgang Pfutzner, Thilo Jakob, Gregers R. Andersen, Edzard Spillner
Summary: This study provides evidence for the relevance of N-glycan recognition in T(H)2 responses and suggests that IgE and IgG antibodies to ubiquitous carbohydrate epitopes can be equivalent to those directed against proteinaceous epitopes with clinical implications.
Review
Immunology
Dennis Vestergaard Pedersen, Josefine Lorentzen, Gregers Rom Andersen
Summary: This article reviews the recent progress in the structure determination of alternative pathway protein FP, highlighting the regions involved in the interactions between C3b, factor B, and FP. The study also sheds light on the relationship between FP activity and its oligomerization state, and discusses the structural basis for FP deficiency and tick-mediated inhibition. Overall, the accumulated structural knowledge provides a comprehensive basis for understanding molecular interactions involving FP and its role in various pathological conditions.
IMMUNOLOGICAL REVIEWS
(2023)
Article
Chemistry, Multidisciplinary
Jing Li, Bintong Huang, Yuanhao Wang, Aijia Li, Yong Wang, Yangyang Pan, Jia Chai, Ze Liu, Yueming Zhai
Summary: The single-molecule technique for investigating unlabeled proteins in solution is challenging, but nanopore sensing offers a label-free tool for collecting structural information. This study developed a reliable method to convert a silicon nitride nanopore into a stable nanonet platform for single-entity sensing. The nanonet provides more structural information and captures the UV-light-induced structural-change process of individual proteins.
ADVANCED MATERIALS
(2023)
Article
Biochemistry & Molecular Biology
Fia B. Larsen, Matteo Cagiada, Jonas Dideriksen, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Catechol-O-methyltransferase (COMT) is an important enzyme involved in the metabolism of neurotransmitters and catecholamine drugs, and its variation can affect pharmacokinetics and drug availability.
Review
Biotechnology & Applied Microbiology
Yixin Rong, Sheila Ingemann Jensen, Kresten Lindorff-Larsen, Alex Toftgaard Nielsen
Summary: The expression of correctly folded and functional heterologous proteins is crucial in biotechnological production processes. Bacterial platform organisms like E. coli are commonly used due to their proven suitability at an industrial scale, but can suffer from protein aggregation and low functional protein levels. This review explores cellular mechanisms influencing protein folding and expression across different organisms, and discusses experimental methods to improve protein folding, such as codon optimization and chaperone co-production.
BIOTECHNOLOGY ADVANCES
(2023)
Article
Biochemistry & Molecular Biology
Caroline Kampmeyer, Martin Gronbaek-Thygesen, Nicole Oelerich, Michael H. Tatham, Matteo Cagiada, Kresten Lindorff-Larsen, Wouter Boomsma, Kay Hofmann, Rasmus Hartmann-Petersen
Summary: Lysine is a common amino acid in the human proteome, but there are proteins that lack lysine residues. These lysine deserts are common in intrinsically disordered proteins involved in the ubiquitin-proteasome system. Introducing lysine residues can increase ubiquitylation of these proteins, and their stability and function may be affected. This avoidance of lysine residues may be an evolutionary mechanism to prevent unnecessary ubiquitylation in proteins closely involved with the ubiquitylation machinery.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Medicine, Research & Experimental
Maria Lange Pedersen, Dennis Vestergaard Pedersen, Mikael Becher Lykkegaard Winkler, Heidi Gytz Olesen, Ole Schmeltz Sogaard, Lars Ostergaard, Nick Stub Laursen, Anna Halling Folkmar Rahimic, Martin Tolstrup
Summary: The complement system, an important part of the innate immune response, can be utilized to eliminate HIV-1-infected cells. Researchers developed a new therapeutic approach, a bispecific complement engager (BiCE), which can direct complement activity to the surface of HIV-1-infected cells. This BiCE has shown the ability to increase complement deposition and mediate complement-dependent cytotoxicity (CDC) of HIV-1-infected cells.
EMBO MOLECULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Kristoffer E. Johansson, Kresten Lindorff-Larsen, Jakob R. Winther
Summary: Identifying amino acid substitutions that improve both stability and function of a protein is a challenge in protein engineering. The Global Multi-Mutant Analysis (GMMA) method is used to identify beneficial substitutions across a large library of protein variants by analyzing multiply-substituted variants. Experimental results showed that the top-ranking substitutions progressively enhanced the function of GFP. Large libraries of multiply-substituted variants could provide valuable information for protein engineering.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jianqiang Mu, Chenyang Xue, Lei Fu, Zongjun Yu, Minhan Nie, Mengqi Wu, Xinmeng Chen, Kun Liu, Ruiqian Bu, Ying Huang, Baisheng Yang, Jianming Han, Qianru Jiang, Kevin C. Chan, Ruhong Zhou, Huilin Li, Ancheng Huang, Yong Wang, Zhongmin Liu
Summary: ATP13A2 is a lysosomal polyamine transporter with mutations associated with diseases such as juvenile-onset Parkinson's disease. The authors have determined the structures of human ATP13A2 in six intermediate states, providing insights into its conformational cycle. These findings contribute to the understanding of how ATP13A2 transports polyamines, which is important for ATP13A2-related diseases.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Yunyun Wang, Zhenni Li, Xinyu Wang, Ziyuan Zhao, Li Jiao, Ruming Liu, Keying Wang, Rui Ma, Yang Yang, Guo Chen, Yong Wang, Xin Bian
Summary: This study investigates the molecular basis of membrane association by the SMP domain of extended synaptotagmin (E-Syt) through in vitro DNA brick-assisted lipid transfer assays and molecular dynamics simulations. The results show that the SMP domain recognizes the highly curved subdomain of the tubular ER and the acidic-lipid-enriched plasma membrane for efficient lipid transfer. These findings support a model for the action of the SMP domain at membrane contact sites (MCSs).
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Moritz Lasse, Jamal El Saghir, Celine C. Berthier, Sean Eddy, Matthew Fischer, Sandra D. Laufer, Dominik Kylies, Arvid Hutzfeldt, Lena Lydie Bonin, Bernhard Dumoulin, Rajasree Menon, Virginia Vega-Warner, Felix Eichinger, Fadhl Alakwaa, Damian Fermin, Anja M. Billing, Akihiro Minakawa, Phillip J. McCown, Michael P. Rose, Bradley Godfrey, Elisabeth Meister, Thorsten Wiech, Mercedes Noriega, Maria Chrysopoulou, Paul Brandts, Wenjun Ju, Linda Reinhard, Elion Hoxha, Florian Grahammer, Maja T. Lindenmeyer, Tobias B. Huber, Hartmut Schlueter, Steffen Thiel, Laura H. Mariani, Victor G. Puelles, Fabian Braun, Matthias Kretzler, Fatih Demir, Jennifer L. Harder, Markus M. Rinschen
Summary: Kidney organoids are a promising model for studying kidney disease. By analyzing the proteome and transcriptome of the organoids, researchers found that older organoids deposit more extracellular matrix and express fewer glomerular proteins. Treatment with TNF-α resulted in differential expression of 322 proteins, including cytokines and complement components. Integration of transcriptomic data revealed that these proteins were associated with poorer clinical outcomes in proteinuric kidney disease patients. This study demonstrates the functional relevance of kidney organoids in modeling human kidney disease.
NATURE COMMUNICATIONS
(2023)
Correction
Biochemistry & Molecular Biology
Rasmus K. Jensen, Rasmus Pihl, Trine A. F. Gadeberg, Jan K. Jensen, Kasper R. Andersen, Steffen Thiel, Nick S. Laursen, Gregers R. Andersen
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Cell Biology
Mengqi Wu, Cang Wu, Tiefeng Song, Kewu Pan, Yong Wang, Zhongmin Liu
Summary: Using cryo-electron microscopy, we obtained six structures of human SPCA1 in intermediate states, revealing a complete conformational cycle. Molecular dynamics simulations further elucidated the structural basis of Ca2+ entry and release in hSPCA1. Our findings uncover unique conformational changes during ATP binding and phosphorylation, as well as a distinct Ca2+ release mechanism induced by the separation of transmembrane helices 4L and 6. Additionally, we determined the elusive CaE2P state of P-type IIA ATPases, providing important insights into the Ca2+ transport cycle.
Article
Chemistry, Multidisciplinary
Dante Guldbrandsen Andersen, Andreas Botker Pedersen, Martin Hogholm Jorgensen, Mireia Casanovas Montasell, Ane Bretschneider Sogaard, Gal Chen, Avi Schroeder, Gregers Rom Andersen, Alexander N. Zelikin
Summary: In this study, synthetic cells with an artificial signaling pathway connecting an extracellular trigger event to the activation of intracellular transcription are engineered. The results highlight the importance of cellularity and demonstrate a significant step towards the design of synthetic cells with responsive behavior, moving towards life-like cell mimics.
ADVANCED MATERIALS
(2023)