Ekaterina I Mokhonova,Daniel Helzer,Ravinder Malik,Hafsa Mamsa,Jackson Walker,Mark Maslanka,Tess S Fleser,Mohammad H Afsharinia,Shiheng Liu,Johan Holmberg,Z Hong Zhou,Eric J Deeds,Kirk C Hansen,Elizabeth M McNally,Rachelle H Crosbie
{"title":"Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.","authors":"Ekaterina I Mokhonova,Daniel Helzer,Ravinder Malik,Hafsa Mamsa,Jackson Walker,Mark Maslanka,Tess S Fleser,Mohammad H Afsharinia,Shiheng Liu,Johan Holmberg,Z Hong Zhou,Eric J Deeds,Kirk C Hansen,Elizabeth M McNally,Rachelle H Crosbie","doi":"10.1172/jci187868","DOIUrl":"https://doi.org/10.1172/jci187868","url":null,"abstract":"The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well-established that genetic mutations that disrupt the structural integrity of DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25-kDa tetraspanin-like protein, anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protect the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rudy J Castellani,Hinda Najem,Amy B Heimberger,Pouya Jamshidi
{"title":"Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy.","authors":"Rudy J Castellani,Hinda Najem,Amy B Heimberger,Pouya Jamshidi","doi":"10.1172/jci195137","DOIUrl":"https://doi.org/10.1172/jci195137","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"606 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ramon U Jin,Yuanwei Xu,Tung-Shing Lih,Yang-Zhe Huang,Toni M Nittolo,Blake E Sells,Olivia M Dres,Jean S Wang,Qing Kay Li,Hui Zhang,Jason C Mills
{"title":"SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett's esophagus development.","authors":"Ramon U Jin,Yuanwei Xu,Tung-Shing Lih,Yang-Zhe Huang,Toni M Nittolo,Blake E Sells,Olivia M Dres,Jean S Wang,Qing Kay Li,Hui Zhang,Jason C Mills","doi":"10.1172/jci190374","DOIUrl":"https://doi.org/10.1172/jci190374","url":null,"abstract":"Esophageal adenocarcinoma (EA) is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2∆/∆; ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g., Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression is likely an initiating step in progression to BE and thence to EA.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Megan E Capozzi,David Bouslov,Ashot Sargsyan,Michelle Y Chan,Sarah M Gray,Katrina Viloria,Akshay Bareja,Jonathan D Douros,Sophie L Lewandowski,Jason Cl Tong,Annie Hasib,Federica Cuozzo,Elizabeth C Ross,Matthew W Foster,Lee S Weinstein,Mehboob A Hussain,Matthew J Merrins,Francis S Willard,Mark O Huising,Kyle W Sloop,David J Hodson,David A D'Alessio,Jonathan E Campbell
{"title":"β-cell Gɑs signaling is critical for physiological and pharmacological enhancement of insulin secretion.","authors":"Megan E Capozzi,David Bouslov,Ashot Sargsyan,Michelle Y Chan,Sarah M Gray,Katrina Viloria,Akshay Bareja,Jonathan D Douros,Sophie L Lewandowski,Jason Cl Tong,Annie Hasib,Federica Cuozzo,Elizabeth C Ross,Matthew W Foster,Lee S Weinstein,Mehboob A Hussain,Matthew J Merrins,Francis S Willard,Mark O Huising,Kyle W Sloop,David J Hodson,David A D'Alessio,Jonathan E Campbell","doi":"10.1172/jci183741","DOIUrl":"https://doi.org/10.1172/jci183741","url":null,"abstract":"The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors coordinate β-cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gɑs protein and generation of intracellular cyclic adenosine monophosphate (cAMP). However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G-proteins and β-arrestin proteins. Here, the importance of Gɑs signaling was tested in mice with conditional, post-developmental β-cell deletion of Gnas (encoding Gɑs) under physiological and pharmacological conditions. Deletion of Gɑs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine and IBMX. In the absence of Gɑs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gɑq signaling. Collectively, these findings validate a central role for cAMP to mediate incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gɑs that causes both fasting hyperglycemia and glucose intolerance.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dae-Seok Kim,Toshiharu Onodera,Jan-Bernd Funcke,Kyounghee Min,Qingzhang Zhu,Qian Lin,Shiuhwei Chen,Chanmin Joung,Min Kim,R Max Wynn,Joselin Velasco,Charlotte Lee,Megan Virostek,Chao Li,Philipp E Scherer
{"title":"Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice.","authors":"Dae-Seok Kim,Toshiharu Onodera,Jan-Bernd Funcke,Kyounghee Min,Qingzhang Zhu,Qian Lin,Shiuhwei Chen,Chanmin Joung,Min Kim,R Max Wynn,Joselin Velasco,Charlotte Lee,Megan Virostek,Chao Li,Philipp E Scherer","doi":"10.1172/jci187202","DOIUrl":"https://doi.org/10.1172/jci187202","url":null,"abstract":"Pro-inflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the anti-inflammatory adenoviral RIDα/β protein complex in a cell type-specific manner. Suppression of adipocyte inflammation (\"RIDad mice\") in a mammary tumor model driven by MMTV-PyMT (\"PyMT-RIDad mice\") led to an elevated number of tumor-associated macrophages (TAMs) and upregulation of immunoregulatory molecules in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (\"RIDMMTV mice\") decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TianMeng Xu,Rachel Heon-Roberts,Travis Moore,Patricia Dubot,Xuefang Pan,Tianlin Guo,Christopher W Cairo,Rebecca J Holley,Brian Bigger,Thomas M Durcan,Thierry Levade,Jerôme Ausseil,Bénédicte Amilhon,Alexei Gorelik,Bhushan Nagar,Shaukat Khan,Shunji Tomatsu,Luisa Sturiale,Angelo Palmigiano,Iris Röckle,Hauke Thiesler,Herbert Hildebrandt,Domenico Garozzo,Alexey V Pshezhetsky
{"title":"Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain proteins hypersialylation.","authors":"TianMeng Xu,Rachel Heon-Roberts,Travis Moore,Patricia Dubot,Xuefang Pan,Tianlin Guo,Christopher W Cairo,Rebecca J Holley,Brian Bigger,Thomas M Durcan,Thierry Levade,Jerôme Ausseil,Bénédicte Amilhon,Alexei Gorelik,Bhushan Nagar,Shaukat Khan,Shunji Tomatsu,Luisa Sturiale,Angelo Palmigiano,Iris Röckle,Hauke Thiesler,Herbert Hildebrandt,Domenico Garozzo,Alexey V Pshezhetsky","doi":"10.1172/jci177430","DOIUrl":"https://doi.org/10.1172/jci177430","url":null,"abstract":"Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII, associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brains of MPS patients and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe to be a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"608 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anand Sripada,Divya Verma,Rangati Varma,Kapil Sirohi,Carolyn Kwiat,Mohini Pathria,Mukesh Verma,Anita Sahu,Vamsi P Guntur,Laurie A Manka,Brian Vestal,Camille M Moore,Richard J Martin,Magdalena M Gorska,John Cambier,Andrew Getahun,Rafeul Alam
{"title":"Allergens abrogate anti-inflammatory DNA effects and unmasks macrophage-driven neutrophilic asthma via ILC2/STING/TNF signaling.","authors":"Anand Sripada,Divya Verma,Rangati Varma,Kapil Sirohi,Carolyn Kwiat,Mohini Pathria,Mukesh Verma,Anita Sahu,Vamsi P Guntur,Laurie A Manka,Brian Vestal,Camille M Moore,Richard J Martin,Magdalena M Gorska,John Cambier,Andrew Getahun,Rafeul Alam","doi":"10.1172/jci187907","DOIUrl":"https://doi.org/10.1172/jci187907","url":null,"abstract":"The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"623 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1.","authors":"Lei Cao,Jie Zhang,Liwen Yu,Wei Yang,Wenqian Qi,Ruiqing Ren,Yapeng Liu,Yonghao Hou,Yu Cao,Qian Li,Xiaohong Wang,Zhengguo Zhang,Bo Li,Wenhai Sui,Yun Zhang,Chengjiang Gao,Cheng Zhang,Meng Zhang","doi":"10.1172/jci186509","DOIUrl":"https://doi.org/10.1172/jci186509","url":null,"abstract":"Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria L Allende,Mari Kono,Y Terry Lee,Samantha M Olmsted,Vienna Huso,Jenna Y Bakir,Florencia Pratto,Cuiling Li,Colleen Byrnes,Galina Tuymetova,Hongling Zhu,Cynthia J Tifft,Richard L Proia
{"title":"CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice.","authors":"Maria L Allende,Mari Kono,Y Terry Lee,Samantha M Olmsted,Vienna Huso,Jenna Y Bakir,Florencia Pratto,Cuiling Li,Colleen Byrnes,Galina Tuymetova,Hongling Zhu,Cynthia J Tifft,Richard L Proia","doi":"10.1172/jci183434","DOIUrl":"https://doi.org/10.1172/jci183434","url":null,"abstract":"Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α-subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with a small guide RNA (sgRNA) to correct the HEXA c.805G>A mutation. Base editing in LOTS patient fibroblasts successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurological manifestations, and reduced lifespan. Treatment of LOTS mice with the neurotropic virus AAV-PHP.eB carrying the ABE and an sgRNA targeting the LOTS point mutation partially corrected the c.805G>A mutation in the CNS, significantly increased brain β-hexosaminidase activity, and substantially reduced GM2 ganglioside accumulation in the brain. Moreover, the therapy delayed symptom onset and significantly extended median lifespan. These findings highlight the potential of base editing as an effective treatment for LOTS and its broader applicability to other lysosomal storage disorders.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The secret life of complement: challenges and opportunities in exploring functions of the complosome in disease.","authors":"Tilo Freiwald,Behdad Afzali","doi":"10.1172/jci188350","DOIUrl":"https://doi.org/10.1172/jci188350","url":null,"abstract":"The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound impact on disease. Current complement-targeting therapeutics for clinical use almost exclusively target the complement system in circulation. However, recent discoveries have demonstrated that complement is not only liver derived and plasma operative, but also synthesized and activated inside many cells locally within tissues, performing noncanonical, cell-autonomous intracellular functions, collectively referred to as the complosome. These intracellular complement pathways are distinct from the classical plasma-based system and critical for regulating fundamental cellular processes, including metabolism, gene transcription, autophagy, and the activation and resolution of inflammation. This Review explores the emerging roles of the complosome and current knowledge regarding its relation to human diseases, highlighting evidence across organ systems and disease states, including the kidneys, digestive tract, lungs, heart, CNS, musculoskeletal system, skin, and cancer. We also review current scientific approaches for detecting and functionally investigating the complosome, addressing challenges such as technological limitations and the need for advanced experimental models to delineate its tissue-specific roles. Finally, we discuss central unanswered questions critical for developing innovative therapeutic strategies targeting intracellular complement pathways. These strategies hold potential to modulate disease-specific mechanisms while preserving systemic complement activity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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