The FEBS journal最新文献_第5页

Loss of carbohydrate sulfotransferase 6 function leads to macular corneal dystrophy phenotypes and skeletal defects in zebrafish.

The FEBS journal Pub Date : 2024-12-06 DOI: 10.1111/febs.17337

Merve Basol, Esra Ersoz-Gulseven, Helin Ozaktas, Sibel Kalyoncu, Canan Asli Utine, Gulcin Cakan-Akdogan

{"title":"Loss of carbohydrate sulfotransferase 6 function leads to macular corneal dystrophy phenotypes and skeletal defects in zebrafish.","authors":"Merve Basol, Esra Ersoz-Gulseven, Helin Ozaktas, Sibel Kalyoncu, Canan Asli Utine, Gulcin Cakan-Akdogan","doi":"10.1111/febs.17337","DOIUrl":"https://doi.org/10.1111/febs.17337","url":null,"abstract":"The carbohydrate sulfotransferase 6 (chst6) gene is linked to macular corneal dystrophy (MCD), a rare disease that leads to bilateral blindness due to the accumulation of opaque aggregates in the corneal stroma. chst6 encodes for a keratan sulfate proteoglycan (KSPG) specific sulfotransferase. MCD patients lose sulfated KSPGs (cKS) in the cornea and the serum. The significance of serum cKS loss has not been understood. Zebrafish cornea structure is similar to that of humans and it contains high levels of sulfated cKS in the stroma. Here, zebrafish chst6 is shown to be expressed in the cornea and head structures of the embryos. An animal model of MCD is developed by generating chst6 mutant animals with CRISPR/Cas9-mediated gene editing. The dramatic decrease in cKS epitopes in the mutants was shown with ELISA and immunofluorescence. Morphological defects or alterations of jaw cartilage were detected in a minor fraction of the mutant larvae. Loss of cKS epitopes and morphological defects was fully rescued with wild-type chst6. Mutant adult zebrafish displayed all clinical manifestations of MCD, while a fraction also displayed jaw and skeleton defects. Opaque accumulations formed in the eye, which were alcian blue positive. Loss of cKS in the corneal stroma and a decrease in corneal thickness were shown. Interestingly, alteration of transforming growth factor beta-induced (BIGH3) expression which was not described in patients was also observed. This is the first report of an MCD model in a genetically tractable organism, providing a preclinical model and insight into the importance of KSPG sulfation for proper skeletal morphogenesis.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789762","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}

引用次数: 0

Rewarding excellence: the 2024 FEBS Journal Richard Perham prize.

The FEBS journal Pub Date : 2024-12-06 DOI: 10.1111/febs.17344

Thomas Minshull, Hajrah Khawaja, Seamus Martin, Julija Hmeljak

引用次数: 0

FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.

The FEBS journal Pub Date : 2024-12-06 DOI: 10.1111/febs.17345

Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss

{"title":"FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.","authors":"Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss","doi":"10.1111/febs.17345","DOIUrl":"https://doi.org/10.1111/febs.17345","url":null,"abstract":"This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789749","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}

引用次数: 0

In conversation with Alexander Wlodawer.

The FEBS journal Pub Date : 2024-12-06 DOI: 10.1111/febs.17322

Alexander Wlodawer, Julija Hmeljak

引用次数: 0

Solving the puzzle of copper trafficking in Trypanosoma cruzi: candidate genes that can balance uptake and toxicity.

The FEBS journal Pub Date : 2024-12-05 DOI: 10.1111/febs.17340

Marcelo L Merli, María G Mediavilla, Xinyu Zhu, Paul A Cobine, Julia A Cricco

{"title":"Solving the puzzle of copper trafficking in Trypanosoma cruzi: candidate genes that can balance uptake and toxicity.","authors":"Marcelo L Merli, María G Mediavilla, Xinyu Zhu, Paul A Cobine, Julia A Cricco","doi":"10.1111/febs.17340","DOIUrl":"https://doi.org/10.1111/febs.17340","url":null,"abstract":"Trypanosoma cruzi, the causative agent of Chagas disease, depends on acquiring nutrients and cofactors, such as copper (Cu), from different hosts. Cu is essential for aerobic organisms, but it can also be toxic, and so its transport and storage must be regulated. In the present study, we characterized the effects of changes in Cu availability on growth behavior, intracellular ion content and oxygen consumption. Our results show that copper is essential for epimastigote proliferation and for the metacyclogenesis process. On the other hand, intracellular amastigotes suffered copper stress during infection. In addition, we identify gene products potentially involved in copper metabolism. Orthologs of the highly conserved P-type Cu ATPases involved in copper export and loading of secreted enzymes were identified and named T. cruzi Cu P-type ATPase (TcCuATPase). TcCuATPase transcription is upregulated during infective stages and following exposure to copper chelators in the epimastigote stage. Homolog sequences for the high affinity import protein CTR1 were not found. Instead, we propose that the T. cruzi iron transporter (TcIT), a ZIP family transporter, could be involved in copper uptake based on transcriptional response to copper availability. Further canonical copper targets (based on homology to yeast and mammals) such as the T. cruzi ferric reductase (TcFR) and the cupro-oxidase TcFet3 are upregulated during infective stages and under conditions of intracellular copper deficiency. In sum, copper metabolism is essential for the life cycle of T. cruzi. Even though cytosolic copper chaperons were not identified, we propose a previously undescribed model for copper transport and intracellular distribution in T. cruzi, including some conserved factors such as TcCuATPase, as well as others such as TcFR and TcIT, playing novel functions.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788323","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}

引用次数: 0

Deciphering the tight metabolite-level regulation of glucose-1-phosphate adenylyltransferase (GlgC) for glycogen synthesis in cyanobacteria.

The FEBS journal Pub Date : 2024-12-05 DOI: 10.1111/febs.17348

Kenric Lee, Sofia Doello, Martin Hagemann, Karl Forchhammer

引用次数: 0

Rational engineering of a highly active and resilient α-carbonic anhydrase from the hydrothermal vent species Persephonella hydrogeniphila.

The FEBS journal Pub Date : 2024-12-05 DOI: 10.1111/febs.17346

Colleen Varaidzo Manyumwa, Chenxi Zhang, Carsten Jers, Ivan Mijakovic

{"title":"Rational engineering of a highly active and resilient α-carbonic anhydrase from the hydrothermal vent species Persephonella hydrogeniphila.","authors":"Colleen Varaidzo Manyumwa, Chenxi Zhang, Carsten Jers, Ivan Mijakovic","doi":"10.1111/febs.17346","DOIUrl":"https://doi.org/10.1111/febs.17346","url":null,"abstract":"Carbonic anhydrases (CAs) are ideal catalysts for carbon dioxide sequestration in efforts to alleviate climate change. Here, we report the characterisation of three α-CAs that originate from the thermophilic bacteria Persephonella hydrogeniphila (PhyCA), Persephonella atlantica (PaCA), and Persephonella sp. KM09-Lau-8 (PlauCA) isolated from hydrothermal vents. The three α-Cas, showing high sequence similarities, were produced in Escherichia coli, purified and characterised. Surprisingly, they revealed very different behaviours with regards to their thermostability profiles. PhyCA presented a more stable thermostability profile amongst the three, thus we chose it for rational engineering to improve it further. PhyCA's residue K88, a proton transfer residue in α-CAs, was mutated to His, Ala, Gln and Tyr. A 4-fold activity improvement was noted for variants K88H and K88Q at 30 °C, owing to the higher proton transfer efficiency of the replacement proton transfer residues. K88Q also proved more stable than PhyCA. K88Y did not increase activity, but notably increased thermal stability, with this enzyme variant retaining 50% of its initial activity after incubation for 1 h at 90 °C. Removal of the two main proton shuttles (variant H85A_K88A) resulted in diminished activity of the enzyme. Molecular dynamics simulations performed for PhyCA and all its variants revealed differences in residue fluctuations, with K88A resulting in a general reduction in root mean square fluctuation (RMSF) of active site residues as well as most of the CA's residues. Its specific activity and stability in turn increased compared to the wild type.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788322","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}

引用次数: 0

Depletion of Tregs from CD4⁺ CAR-T cells enhances the tumoricidal effect of CD8⁺ CAR-T cells in anti-CD19 CAR-T therapy.

The FEBS journal Pub Date : 2024-12-04 DOI: 10.1111/febs.17326

Yunyan Sun, Jinyan Liu, Dong Zhan, Jia Wei, Li XianShi, Rui Zhang, Ci Duan, Disi Zhang, Xiaorong Tang, Tuo Lin, Limei Li, Xun Lai

{"title":"Depletion of Tregs from CD4+ CAR-T cells enhances the tumoricidal effect of CD8+ CAR-T cells in anti-CD19 CAR-T therapy.","authors":"Yunyan Sun, Jinyan Liu, Dong Zhan, Jia Wei, Li XianShi, Rui Zhang, Ci Duan, Disi Zhang, Xiaorong Tang, Tuo Lin, Limei Li, Xun Lai","doi":"10.1111/febs.17326","DOIUrl":"https://doi.org/10.1111/febs.17326","url":null,"abstract":"Chimeric antigen receptor T (CAR-T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy. However, some patients may develop resistance to CAR-T treatment, underscoring the importance of optimizing CAR-T design to enhance responsiveness. Here, we investigated the impact of different subpopulations in anti-CD19 CAR-T cells on the tumoricidal effect. Different populations of anti-CD19 CAR-T cells were isolated by magnetic-activated cell sorting (MACS). Their lytic activities on the acute lymphocytic leukemia cell line SUP-B15 and diffuse large B-cell lymphoma EB-3 cell line were examined in a co-culture system. The anti-tumorigenic outcome of different CAR-T cell compositions was evaluated in a xenograft mouse model of EB-3 cells. CD8+CAR-T cells exhibited the most potent tumoricidal activity against SUP-B15 and EB-3 cells. Additionally, CD4+ T helper cells enhanced the lytic effects of CD8+ CAR-T cells by increasing the availability of interleukin-2 (IL-2). Depleting CD25+Treg (T regulatory) cells from CD4+CAR-T population further augmented the tumoricidal activity of CD8+CAR-T cells by preventing IL-2 deprivation. Consistently, in vivo experiments demonstrated that the CD4+CD25+ Treg population dampened the antitumor activity of CD8+CAR-T cells, while depletion of Tregs from CD4+CAR-T cells enhanced the tumoricidal effect. These findings emphasize the potential role of CAR Treg cells in therapeutic resistance, suggesting that the depletion of Tregs in the anti-CD19 CAR-T population may serve as a strategy to augment the anticancer effect of CD8+CAR-T cells.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782325","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}

引用次数: 0

Coordination among cytoskeletal organization, cell contraction, and extracellular matrix development is dependent on LOX for aneurysm prevention.

The FEBS journal Pub Date : 2024-12-04 DOI: 10.1111/febs.17341

Rohtem Aviram, Shelly Zaffryar-Eilot, Anna Kaganovsky, Anas Odeh, Shay Melamed, Ruslana Militsin, Lavi Coren, Cameron B Pinnock, Ariel Shemesh, Raz Palty, Santhi K Ganesh, Peleg Hasson

{"title":"Coordination among cytoskeletal organization, cell contraction, and extracellular matrix development is dependent on LOX for aneurysm prevention.","authors":"Rohtem Aviram, Shelly Zaffryar-Eilot, Anna Kaganovsky, Anas Odeh, Shay Melamed, Ruslana Militsin, Lavi Coren, Cameron B Pinnock, Ariel Shemesh, Raz Palty, Santhi K Ganesh, Peleg Hasson","doi":"10.1111/febs.17341","DOIUrl":"10.1111/febs.17341","url":null,"abstract":"Distinct and seemingly independent cellular pathways affecting intracellular machinery or extracellular matrix (ECM) deposition and organization have been implicated in aneurysm formation. One of the key genes associated with this pathology in both humans and mice is lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells. We find that cytoskeletal organization is lost following Lox deletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light-chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably, they provide a link between multiple processes leading to aneurysm formation, suggesting LOX coordinates ECM development, cytoskeletal organization, and cell contraction required for media development and function.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782324","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}

引用次数: 0

Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice.

The FEBS journal Pub Date : 2024-12-03 DOI: 10.1111/febs.17339

Ryo Inagaki, Satomi Kita, Nozomu Niwa, Kohji Fukunaga, Takahiro Iwamoto, Shigeki Moriguchi

{"title":"Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice.","authors":"Ryo Inagaki, Satomi Kita, Nozomu Niwa, Kohji Fukunaga, Takahiro Iwamoto, Shigeki Moriguchi","doi":"10.1111/febs.17339","DOIUrl":"https://doi.org/10.1111/febs.17339","url":null,"abstract":"Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3+/-) mice. NCX3+/- mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3+/- mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3+/- mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3+/- mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3+/- mice.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776089","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}

引用次数: 0