The FEBS journal最新文献_第4页

SASH1 is a novel binding partner to disassemble Caskin1 tandem SAM homopolymer through heterogeneous SAM-SAM interaction.

The FEBS journal Pub Date : 2024-12-17 DOI: 10.1111/febs.17354

Yanhui Wang, Qiangou Chen, Cang Wu, Yuzhen Ding, Lin Yuan, Ziyi Wang, Yu Chen, Jianchao Li, Zhongmin Liu, Kang Xiao, Wei Liu

{"title":"SASH1 is a novel binding partner to disassemble Caskin1 tandem SAM homopolymer through heterogeneous SAM-SAM interaction.","authors":"Yanhui Wang, Qiangou Chen, Cang Wu, Yuzhen Ding, Lin Yuan, Ziyi Wang, Yu Chen, Jianchao Li, Zhongmin Liu, Kang Xiao, Wei Liu","doi":"10.1111/febs.17354","DOIUrl":"https://doi.org/10.1111/febs.17354","url":null,"abstract":"Calcium/calmodulin-dependent serine protein kinase (CASK) interaction protein 1/2 (Caskin1/2) is essential neuronal synaptic scaffold protein in nervous system development. Knockouts of Caskin1/2 display severe deficits in novelty recognition and spatial memory. The tandem sterile alpha motif (SAM) domains of Caskin1/2, also conserved in their Drosophila homolog Ckn, are known to form homopolymers, yet their dynamic regulation mechanism remains unclear. In this study, SAM and SH3 domain-containing protein 1 (SASH1) was first identified as a novel binding partner of Caskin1/2 through yeast two-hybrid (Y2H) screening. The SAM-SAM interaction between SASH1 and Caskin1 was biochemically characterized by size-exclusion chromatography (SEC), isothermal titration calorimetry (ITC), and glutathione-S-transferase (GST) pull-down and co-immunoprecipitation (co-IP) assays. Structural insights from AlphaFold2-predicted models of the Caskin1-SAMs/SASH1-SAM1 complex, along with mutagenesis validations, revealed key residues at the end-helix (EH)/mid-loop (ML) interface for this interaction. More interestingly, the Caskin1-SAMs homopolymer can be disrupted by the SAM-SAM interaction, which was consistently verified by using sedimentation, transmission electron microscopy (TEM), and immunofluorescence (IF) staining in heterologous cell lines. In summary, our findings provide a solid biochemical basis for the Caskin1/SASH1 interaction and propose a potential mechanism for regulating Caskin1/2 homopolymerization via SAM-SAM interactions. More importantly, the principle governing SAM homopolymer depolymerization is generalized via suggesting two distinct types of heterogeneous SAM-SAM interactions, offering fresh insights into SAM domain-mediated homopolymerization and depolymerization.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840699","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

Porphyromonas gingivalis outer membrane vesicles increase vascular permeability by inducing stress fiber formation and degrading vascular endothelial-cadherin in endothelial cells.

The FEBS journal Pub Date : 2024-12-17 DOI: 10.1111/febs.17349

Mana Mekata, Kaya Yoshida, Ayu Takai, Yuka Hiroshima, Ayu Ikuta, Mariko Seyama, Kayo Yoshida, Kazumi Ozaki

{"title":"Porphyromonas gingivalis outer membrane vesicles increase vascular permeability by inducing stress fiber formation and degrading vascular endothelial-cadherin in endothelial cells.","authors":"Mana Mekata, Kaya Yoshida, Ayu Takai, Yuka Hiroshima, Ayu Ikuta, Mariko Seyama, Kayo Yoshida, Kazumi Ozaki","doi":"10.1111/febs.17349","DOIUrl":"https://doi.org/10.1111/febs.17349","url":null,"abstract":"Porphyromonas gingivalis (Pg) is a keystone bacterium associated with systemic diseases, such as diabetes mellitus and Alzheimer's disease. Outer membrane vesicles (OMVs) released from Pg have been implicated in systemic diseases by delivering Pg virulence factors to host cells in distant organs and inducing cellular dysfunction. Pg OMVs also have the potential to enter distant organs via the bloodstream. However, the effects of Pg OMVs on the vascular function are poorly understood. Here, we showed that Pg OMVs increase vascular permeability by promoting stress fiber formation and lysosome/endosome-mediated vascular endothelial-cadherin (VEc) degradation in human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs). F-actin, visualized via fluorescein isothiocyanate-phalloidin, became thicker and longer, leading to the formation of radical stress fibers in response to Pg OMVs in HUVECs and HPMECs. Western blotting and quantitative real-time polymerase chain reaction analyses revealed that Pg OMVs decreased VEc protein levels in a gene-independent manner. Pg OMVs enhanced vesicular VEc accumulation in the cytoplasm around lysosome-associated membrane protein 1-positive structures during pretreatment with the lysosomal inhibitor chloroquine. This suggests that Pg OMVs decrease VEc protein levels by accelerating their internalization and degradation via lysosomes and endosomes. A27632 inhibition of Rho kinases impaired the Pg OMV-induced stress fiber formation and VEc degradation, resulting in the recovery of hyperpermeability. These findings provide new insights into the pathogenesis of systemic diseases that are associated with periodontal diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848777","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

More and more pleiotropy within the IL-6 family of cytokines.

The FEBS journal Pub Date : 2024-12-13 DOI: 10.1111/febs.17355

Stefan Rose-John, Simon A Jones

引用次数: 0

Words of advice: how to write the story of a patient for a problem-based learning session in a healthcare education program.

The FEBS journal Pub Date : 2024-12-13 DOI: 10.1111/febs.17343

Andrew D Bergemann, Matthew McMillin, Miriah C Gillispie-Taylor, Gareth Gingell, R Taylor Surles, Rachel Wallace

{"title":"Words of advice: how to write the story of a patient for a problem-based learning session in a healthcare education program.","authors":"Andrew D Bergemann, Matthew McMillin, Miriah C Gillispie-Taylor, Gareth Gingell, R Taylor Surles, Rachel Wallace","doi":"10.1111/febs.17343","DOIUrl":"https://doi.org/10.1111/febs.17343","url":null,"abstract":"Medical education is in the process of a pedagogical revolution. Traditional lectures are playing a progressively smaller role, with more of the content being delivered through student-centered small-group sessions. Problem-based learning (PBL) has become a centerpiece of education for many medical schools, in large part because of its focus on the learners identifying their own knowledge gaps. As junior scientists seek faculty appointments in institutions focused on healthcare education, they will find that skills in PBL are valued by the academic community. Among the necessary skills is the capability to lead efforts in PBL case writing. The cases, each of which is a narrative of a patient's experience of disease, are a critical component of the PBL process, as they trigger learners to follow their curiosity and thereby drive learning. In this article, we outline a clear methodology for educators to follow to create new cases. The described steps provide guidance on making each case powerful to learners through creating immediacy and a sense of the patient as a human being. Guidance is also provided to enable case authors to avoid the common pitfalls, including avoiding the introduction of unintended biases and microaggressions. Importantly, guidance is also provided regarding the best practices to incorporate feedback from content experts. Following the steps in our process promotes a methodical approach to case writing that consistently generates a quality product that enriches student learning.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823030","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

Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera. 利用新型蛋白水解靶向嵌合体靶向降解 PDE4 短型蛋白。

The FEBS journal Pub Date : 2024-12-13 DOI: 10.1111/febs.17359

Yuan Yan Sin, Aoife Giblin, Aleksandra Judina, Punchita Rujirachaivej, Laura G Corral, Eliza Glennon, Zhi Xian Tai, Tian Feng, Eduardo Torres, Alina Zorn, Julia Gorelik, Elka Kyurkchieva, Pa Thai Yenchitsomanus, Cathy Swindlehurst, Kyle Chan, David Stirling, George S Baillie

{"title":"Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera.","authors":"Yuan Yan Sin, Aoife Giblin, Aleksandra Judina, Punchita Rujirachaivej, Laura G Corral, Eliza Glennon, Zhi Xian Tai, Tian Feng, Eduardo Torres, Alina Zorn, Julia Gorelik, Elka Kyurkchieva, Pa Thai Yenchitsomanus, Cathy Swindlehurst, Kyle Chan, David Stirling, George S Baillie","doi":"10.1111/febs.17359","DOIUrl":"https://doi.org/10.1111/febs.17359","url":null,"abstract":"Cyclic AMP (cAMP) has a crucial role in many vital cellular processes and there has been much effort expended in the discovery of inhibitors against the enzyme superfamily that degrades this second messenger, namely phosphodiesterases (PDEs). The journey of competitive PDE inhibitors to the clinic has been hampered by side effects profiles that have resulted from a lack of selectivity for subfamilies and individual isoforms because of high conservation of catalytic site sequences and structures. Here we introduce a proteolysis targeting chimera (PROTAC) that can specifically target a small subset of isoforms from the PDE4 family to send the enzyme for degradation at the proteasome by recruiting a ubiquitin E3 ligase into proximity with the PDE. We constructed our PDE4 PROTAC (KTX207) using a previously characterized PDE4 inhibitor, and we show that evolution of the compound into a PROTAC improves selectivity, potency and enables a long-lasting effect even after the compound is removed from cells after a short treatment duration. Functionally, KTX207 is more effective at increasing cAMP, is 100 times more anti-inflammatory, and is significantly better at reducing the growth in cancer cell models than the PDE4 inhibitor alone. Our study highlights the advantages of targeted degradation versus active-site occupancy for PDE4 inhibition and discusses the potential of this novel pharmacological approach to improve the safety profile of PDE4 inhibition in the future.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823018","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

Membrane anchoring of New Delhi metallo-β-lactamase-1 alters the fitness of Escherichia coli and increases its susceptibility to colistin by inducing outer membrane destabilization.

The FEBS journal Pub Date : 2024-12-10 DOI: 10.1111/febs.17351

Bo Ma, Shan Zhou, Chao Fang, Mingzhi Wang, Xiaoyan Xue, Jianwei Xie, Jiayun Liu, Zheng Hou

{"title":"Membrane anchoring of New Delhi metallo-β-lactamase-1 alters the fitness of Escherichia coli and increases its susceptibility to colistin by inducing outer membrane destabilization.","authors":"Bo Ma, Shan Zhou, Chao Fang, Mingzhi Wang, Xiaoyan Xue, Jianwei Xie, Jiayun Liu, Zheng Hou","doi":"10.1111/febs.17351","DOIUrl":"https://doi.org/10.1111/febs.17351","url":null,"abstract":"New Delhi metallo-β-lactamase-1 (NDM-1)-producing bacteria are resistant to nearly all available β-lactam antibiotics and have become a public health threat. Antibiotic resistance often carries fitness costs, which typically manifest as a reduced bacterial growth rate. Here, we investigated the mechanism of fitness cost in NDM-1-producing bacteria. Our findings revealed that strains expressing blaNDM-1 exhibited a significant growth defect under high osmotic stress. This fitness cost was attributed to the anchoring of NDM-1 to the bacterial outer membrane via its leader peptide, which destabilized the outer membrane. Replacing the membrane-anchoring residue Cys26 in the leader peptide with alanine not only restored outer membrane stability but also ameliorated the bacterial fitness cost. Furthermore, the anchoring of NDM-1 to the membrane increased bacterial susceptibility to the membrane-disrupting antibiotic colistin, both in vitro and in vivo, as confirmed in engineered and clinically isolated strains. In conclusion, membrane anchoring of NDM-1 increased the permeability of the bacterial outer membrane, thereby reducing the fitness of NDM-1-producing bacteria and enhancing their susceptibility to colistin. These results not only elucidate the mechanism of fitness cost associated with NDM-1 but also provide new insights into the rational use of colistin to combat infections caused by NDM-1-producing bacteria.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809031","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

Structural elucidation and characterization of GH29A α-l-fucosidases and the effect of pH on their transglycosylation.

The FEBS journal Pub Date : 2024-12-10 DOI: 10.1111/febs.17347

Yaya Yang, Jesper Holck, Albert Thor Thorhallsson, Cameron J Hunt, Huan Yang, Jens Preben Morth, Anne S Meyer, Birgitte Zeuner

{"title":"Structural elucidation and characterization of GH29A α-l-fucosidases and the effect of pH on their transglycosylation.","authors":"Yaya Yang, Jesper Holck, Albert Thor Thorhallsson, Cameron J Hunt, Huan Yang, Jens Preben Morth, Anne S Meyer, Birgitte Zeuner","doi":"10.1111/febs.17347","DOIUrl":"https://doi.org/10.1111/febs.17347","url":null,"abstract":"GH29A α-l-fucosidases (EC 3.2.1.51) catalyze the release of α-l-fucosyl moieties from the nonreducing end of glycoconjugates by hydrolysis and some also catalyze transglycosylation. The latter is particularly interesting with regard to designing enzymatic synthesis of human milk oligosaccharides (HMOs). We combined the bioinformatics tool conserved unique peptide patterns (CUPP) and phylogenetic clustering to discover new microbial GH29A α-l-fucosidases of the underexplored CUPP group GH29:13.1. Three uncharacterized bacterial enzymes (EaGH29, SeGH29, and PmGH29) and two previously identified GH29A α-l-fucosidases (BF3242 and TfFuc1) were selected for reaction optimization, biochemical, and structural characterization. Kinetics, pH-temperature optima, and substrate preference for 2-chloro-4-nitrophenyl-α-l-fucopyranoside (CNP-α-l-Fuc) and 2'-fucosyllactose (2'FL) were determined. Transglycosylation was favored at high neutral to alkaline pH, especially for EaGH29, SeGH29, TfFuc1, and BF3242, mainly because hydrolysis was decreased. The α-l-fucosidases exhibited medium regioselectivity in transglycosylation, generally forming two out of five detected lacto-N-fucopentaose (LNFP) isomers from 2'FL and lacto-N-tetraose (LNT). Alkaline pH also affected the transglycosylation product regioselectivity of SeGH29, which was also affected by a Leu/Phe exchange in the acceptor binding site. New crystal structures of TfFuc1 and BF3242 showed congruence in active site topology between these two enzymes and contributed to understanding the function of GH29A α-l-fucosidases. Notably, the structural data provide new insight into the role of an Asn residue located between the two catalytic residues in the active site.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809034","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

Editor profile: Lawrence Banks.

The FEBS journal Pub Date : 2024-12-10 DOI: 10.1111/febs.17323

Lawrence Banks

引用次数: 0

Protein import into bacterial endosymbionts and evolving organelles.

The FEBS journal Pub Date : 2024-12-10 DOI: 10.1111/febs.17356

Megan E S Sørensen, Mygg L Stiller, Lena Kröninger, Eva C M Nowack

{"title":"Protein import into bacterial endosymbionts and evolving organelles.","authors":"Megan E S Sørensen, Mygg L Stiller, Lena Kröninger, Eva C M Nowack","doi":"10.1111/febs.17356","DOIUrl":"https://doi.org/10.1111/febs.17356","url":null,"abstract":"Bacterial endosymbionts are common throughout the eukaryotic tree of life and provide a range of essential functions. The intricate integration of bacterial endosymbionts into a host led to the formation of the energy-converting organelles, mitochondria and plastids, that have shaped eukaryotic evolution. Protein import from the host has been regarded as one of the distinguishing features of organelles as compared to endosymbionts. In recent years, research has delved deeper into a diverse range of endosymbioses and discovered evidence for 'exceptional' instances of protein import outside of the canonical organelles. Here we review the current evidence for protein import into bacterial endosymbionts. We cover both 'recently evolved' organelles, where there is evidence for hundreds of imported proteins, and endosymbiotic systems where currently only single protein import candidates are described. We discuss the challenges of establishing protein import machineries and the diversity of mechanisms that have independently evolved to solve them. Understanding these systems and the different independent mechanisms, they have evolved is critical to elucidate how cellular integration arises and deepens at the endosymbiont to organelle interface. We finish by suggesting approaches that could be used in the future to address the open questions. Overall, we believe that the evidence now suggests that protein import into bacterial endosymbionts is more common than generally realized, and thus that there is an increasing number of partnerships that blur the distinction between endosymbiont and organelle.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809033","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

Villin-1 regulates ferroptosis in colorectal cancer progression.

The FEBS journal Pub Date : 2024-12-10 DOI: 10.1111/febs.17350

Bangli Hu, Yixin Yin, Birong Zhang, Siqi Li, Kezhi Li, You Zhou, Qinghua Huang

{"title":"Villin-1 regulates ferroptosis in colorectal cancer progression.","authors":"Bangli Hu, Yixin Yin, Birong Zhang, Siqi Li, Kezhi Li, You Zhou, Qinghua Huang","doi":"10.1111/febs.17350","DOIUrl":"https://doi.org/10.1111/febs.17350","url":null,"abstract":"Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809036","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