Biochemical Journal最新文献

EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression. EZH2通过抑制NRP1抑制自噬，促进结直肠癌的化疗耐药。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-02 DOI: 10.1042/bcj20240607

Hong Deng,Qin Xu,Qiang Zhang,Chunfeng Liu,Lei Ren

{"title":"EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression.","authors":"Hong Deng,Qin Xu,Qiang Zhang,Chunfeng Liu,Lei Ren","doi":"10.1042/bcj20240607","DOIUrl":"https://doi.org/10.1042/bcj20240607","url":null,"abstract":"Colorectal cancer (CRC) is characterized by aggressive tumor growth and chemoresistance, with Enhancer of zeste homolog 2 (EZH2) serving a pivotal role in these processes. However, the mechanisms by which it drives tumor proliferation and therapeutic resistance through autophagy regulation remain unclear. Here, we demonstrated that EZH2 expression is elevated in CRC tissues and cell lines, correlating with chemoresistance and diagnostic potential (Area Under the Curve, AUC = 0.968). EZH2 knockdown markedly reduced CRC cell proliferation, while its overexpression promoted tumor growth and increased resistance to irinotecan. Mechanistically, EZH2 suppressed autophagy in CRC cells, a process linked to chemosensitivity, by directly regulating LC3bI/II expression. Notably, EZH2 enhanced the Neuropilin-1 (NRP1) level by binding to the NRP1 promoter, thereby promoting tumor proliferation and irinotecan resistance through autophagy inhibition. NRP1 depletion partially reversed these effects, underscoring the crucial role of the EZH2-NRP1 axis in CRC. Our findings highlight that targeting the EZH2-NRP1 interaction could represent a novel therapeutic approach to overcoming chemoresistance in CRC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"109 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cytokines from parasites: manipulating host responses by molecular mimicry. 来自寄生虫的细胞因子：通过分子模仿操纵宿主反应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-29 DOI: 10.1042/bcj20253061

Rick M Maizels,Henry J McSorley,Hermelijn H Smits,Peter Ten Dijke,Andrew P Hinck

{"title":"Cytokines from parasites: manipulating host responses by molecular mimicry.","authors":"Rick M Maizels,Henry J McSorley,Hermelijn H Smits,Peter Ten Dijke,Andrew P Hinck","doi":"10.1042/bcj20253061","DOIUrl":"https://doi.org/10.1042/bcj20253061","url":null,"abstract":"Helminth parasites have evolved sophisticated methods for manipulating the host immune response to ensure long-term survival in their chosen niche, for example, by secreting products that interfere with the host cytokine network. Studies on the secretions of Heligmosomoides polygyrus have identified a family of transforming growth factor-β (TGF-β) mimics (TGMs), which bear no primary amino acid sequence similarity to mammalian TGF-β, but functionally replicate or antagonise TGF-β effects in restricted cell types. The prototypic member, TGM1, induces in vitro differentiation of Foxp3+ T regulatory cells and attenuates airway allergic and intestinal inflammation in animal models. TGM1 is one of a family of ten TGM proteins expressed by H. polygyrus. It is a five-domain modular protein in which domains 1-2 bind TGFBR1, and domain 3 binds TGFBR2; domains 4-5 increase its potency by binding a co-receptor, CD44, highly expressed on immune cells. Domains 4-5 are more diverse in other TGMs, which bind co-receptors on cells such as fibroblasts. One variant, TGM6, lacks domains 1-2 and hence cannot transduce a signal but binds TGFBR2 through domain 3 and a co-receptor expressed on fibroblasts through domains 4-5 and blocks TGF-β signalling in fibroblasts and epithelial cells; T cells do not express the co-receptor and are not inhibited by TGM6. Hence, different family members have evolved to act as agonists or antagonists on various cell types. TGMs, which function by molecularly mimicking binding of the host cytokine to the host TGF-β receptors, are examples of highly evolved immunomodulators from parasites, including those that block interleukin (IL)-13 and IL-33 signalling, modulate macrophage and dendritic cell responses and modify host cell metabolism. The emerging panoply and potency of helminth evasion molecules illustrates the range of strategies in play to maintain long-term infections in the mammalian host.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"25 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural characterisation of a cysteine-rich conotoxin, sigma(σ)S-GVIIIA, extracted from the defensive venom of the marine cone snail Conus geographus. 从海锥螺防御毒液中提取的一种富含半胱氨酸的螺毒素sigma(σ) s - gviii的结构特征。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-23 DOI: 10.1042/bcj20240753

Yoshimi Peck,David Wilson,Danica Lennox-Bulow,Julien Giribaldi,Jamie Seymour,Sebastien Dutertre,K Rosengren,Michael Liddell,Norelle Daly

{"title":"Structural characterisation of a cysteine-rich conotoxin, sigma(σ)S-GVIIIA, extracted from the defensive venom of the marine cone snail Conus geographus.","authors":"Yoshimi Peck,David Wilson,Danica Lennox-Bulow,Julien Giribaldi,Jamie Seymour,Sebastien Dutertre,K Rosengren,Michael Liddell,Norelle Daly","doi":"10.1042/bcj20240753","DOIUrl":"https://doi.org/10.1042/bcj20240753","url":null,"abstract":"The activity of the serotonin type 3 (5-HT3) receptor is associated with neurodegenerative, inflammatory and metabolic diseases, neuropsychiatric disorders, and cancer. Structural analysis of modulators of this receptor is likely to aid in future medicinal chemistry studies aimed at developing lead molecules targeting this receptor. Here we report the structure of a cone snail venom peptide that was purified from the crude venom of Conus geographus and shown to be an antagonist of the 5-HT3 receptor more than 25 years ago, sigma(σ)GVIIIA. This lag in structural characterisation studies is likely due to challenges in isolating the native peptide and difficulties in producing synthetic peptide due to the presence of ten cysteine residues involved in five disulfide bonds. Using NMR spectroscopy, we show that σS-GVIIIA adopts a growth factor cystine knot (GFCK) fold. This is the first example of a cone snail venom peptide experimentally determined to contain the GFCK structural motif, and the first example of a 5-HT3 receptor antagonist containing this motif. Our study also highlights complexities in the use of artificial intelligence-based structure prediction models. Peptide structure predictions using AlphaFold 3 were consistent with our NMR structure when the input sequence contained the well-conserved precursor sequence, but inconsistent when the precursor sequence was excluded. AI-based structure prediction of proteins is a rapidly advancing field, but this inconsistency emphasises the need for more experimental structural training data when novel structures are involved, as was the case here for a cysteine-rich peptide.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"34 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction: Lead induces the upregulation of protein arginine methyltransferase 5 possibly by its promoter demethylation. 撤回：铅可能通过启动子去甲基化诱导蛋白精氨酸甲基转移酶5的上调。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-10 DOI: 10.1042/bcj20180167_ret

引用次数: 0

Retraction: Lead induces the upregulation of protein arginine methyltransferase 5 possibly by its promoter demethylation. 撤回：铅可能通过启动子去甲基化诱导蛋白精氨酸甲基转移酶5的上调。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-04-10 DOI: 10.1042/bcj20180009_ret

引用次数: 0

Paraquat resistance mutations have differential effects on plant fitness in two rice cultivars. 抗百草枯突变对两个水稻品种的植株适合度有不同的影响。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-04-08 DOI: 10.1042/BCJ20240683

Jared B Fudge, Teresa B Fitzpatrick

{"title":"Paraquat resistance mutations have differential effects on plant fitness in two rice cultivars.","authors":"Jared B Fudge, Teresa B Fitzpatrick","doi":"10.1042/BCJ20240683","DOIUrl":"https://doi.org/10.1042/BCJ20240683","url":null,"abstract":"Paraquat is a fast-acting non-selective herbicide widely used globally to eradicate weeds. The emergence of weed resistance has fueled the drive to understand molecular mechanistic aspects and develop crops resistant to the herbicide. The transport of paraquat is mediated by members of the L-amino acid transporter family and are prime targets for the development of resistance. However, these transporters also facilitate the transport of natural essential molecules such as polyamines and thiamine (vitamin B1), at least in Arabidopsis, but have not undergone rigorous investigation in crops. Here we report on disruption of the polyamine transporter PUT3 in two japonica rice cultivars. Both rice put3 mutant alleles are resistant to paraquat and display low percentage germination concomitant with altered polyamine profiles whereas thiamine is unchanged. Notwithstanding, seedlings that germinate behave like wild type in the Tainung 67 cultivar, whereas further growth and development is strongly impaired by disruption of PUT3 in the Hwayoung cultivar. The growth phenotype could be complemented by ectopic expression of PUT3, which also restores the polyamine profile thus linking the defects to disruption of the gene. Our study provides biological insight into the divergent characteristics of rice cultivar tissues as a function of their polyamine profile and a warning to exercise caution upon disruption of transporters to facilitate paraquat resistance in crops as this may also lead to severe fitness penalties.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic Interchange of Local Residue-Residue Interactions in the Largely Extended Single Alpha-Helix in Drebrin. 大扩展单α -螺旋中局部残基-残基相互作用的动态交换。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-04-01 DOI: 10.1042/BCJ20253036

Soma Varga, Bálint Ferenc Péterfia, Dániel Dudola, Viktor Farkas, Cy M Jeffries, Perttu Permi, Zoltán Gáspári

{"title":"Dynamic Interchange of Local Residue-Residue Interactions in the Largely Extended Single Alpha-Helix in Drebrin.","authors":"Soma Varga, Bálint Ferenc Péterfia, Dániel Dudola, Viktor Farkas, Cy M Jeffries, Perttu Permi, Zoltán Gáspári","doi":"10.1042/BCJ20253036","DOIUrl":"https://doi.org/10.1042/BCJ20253036","url":null,"abstract":"Single alpha-helices (SAHs) are protein regions with unique mechanical properties, forming long stable monomeric helical structures in solution. To date, only a few naturally occurring SAH regions have been extensively characterized, primarily from myosins, leaving the structural and dynamic variability of SAH regions largely unexplored. Drebrin (developmentally regulated brain protein) contains a predicted SAH segment with unique sequence characteristics, including aromatic residues within the SAH region and a preference for arginine over lysine in its C-terminal half. Using and NMR spectroscopy, combined with SAXS measurements, we demonstrate that the Drebrin-SAH is helical and monomeric in solution. NMR resonance assignment required specific 4D techniques to resolve severe signal overlap resulting from the low complexity and largely helical conformation of the sequence. To further characterize its structure, we generated a structural ensemble consistent with Cα, Cβ chemical shifts and SAXS data, revealing a primarily extended structure with non-uniform helicity. Our results suggest that dynamic rearrangement of salt bridges and potential transient cation-π interactions contribute to the formation and stabilization of both helical and non-helical local conformational states.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aurora A binds to the transactivation domain of c-Myc and recognizes the phosphorylated N-terminal degron motif. Aurora A结合到c-Myc的转激活域并识别磷酸化的n端脱基序。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-03-28 DOI: 10.1042/BCJ20240726

Nidhi Joshi, Katie M Dunleavy, Kaitlin M Beel, Tiffany A Engel, Andrew R Thompson, Felix L John, David D Thomas, Nicholas M Levinson

{"title":"Aurora A binds to the transactivation domain of c-Myc and recognizes the phosphorylated N-terminal degron motif.","authors":"Nidhi Joshi, Katie M Dunleavy, Kaitlin M Beel, Tiffany A Engel, Andrew R Thompson, Felix L John, David D Thomas, Nicholas M Levinson","doi":"10.1042/BCJ20240726","DOIUrl":"https://doi.org/10.1042/BCJ20240726","url":null,"abstract":"The oncoprotein c-Myc is overexpressed or mutated in a large fraction of human cancers. The stability of c-Myc is controlled by phosphorylation of T58 and S62 within a conserved degron motif in the N-terminal transactivation domain, which triggers recruitment of the SCF ubiquitin ligase. The kinase Aurora A (AurA) has been shown to bind to both c-Myc and its paralog N-Myc and to promote their stability by interfering with ubiquitination and degradation. Here we show, using NMR and FRET experiments, that AurA binds to c-Myc through several discrete interactions spanning 145 residues within its transactivation domain. AurA binding to c-Myc is enhanced by phosphorylation of the T58/S62 degron, demonstrating that the kinase recognizes the pool of c-Myc that has been marked for degradation by the ubiquitin proteasome pathway. Although AurA binds to segments of c-Myc flanking the degron, it does not appear to form extensive interactions with the phosphorylated degron itself, potentially leaving it accessible on the AurA surface. These observations establish a foundation for understanding the role of AurA in regulating c-Myc ubiquitination and degradation.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sequence rules for a long SPOP-binding degron required for protein ubiquitylation. 蛋白质泛素化所需的长spop结合降解的序列规则。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-03-27 DOI: 10.1042/BCJ20253041

Linda Makhlouf, Mukul Mishra, Hannah Makhlouf, Iain Manfield, Luca Busino, Elton Zeqiraj

{"title":"Sequence rules for a long SPOP-binding degron required for protein ubiquitylation.","authors":"Linda Makhlouf, Mukul Mishra, Hannah Makhlouf, Iain Manfield, Luca Busino, Elton Zeqiraj","doi":"10.1042/BCJ20253041","DOIUrl":"https://doi.org/10.1042/BCJ20253041","url":null,"abstract":"The adaptor protein, Speckle-type BTB/POZ protein (SPOP), recruits substrates to the cullin-3-subclass of E3 ligase for selective protein ubiquitylation. The Myddosome protein, Myeloid differentiation primary response 88 (MyD88), is ubiquitylated by the SPOP-based E3 ligase to negatively regulate immune signaling, however, the sequence rules for SPOP-mediated substrate engagement and degradation are not fully understood. Here, we show that MyD88 interacts with SPOP through a long degron that contains the established SPOP-binding consensus and an N-terminal site that we name the Q-motif. Based on sequence similarity to MyD88, we show that additional substrates, including Steroid receptor coactivator-3 (SRC-3), SET domain-containing protein 2 (SETD2) and Caprin1, engage SPOP in this manner. We show that the Q-motif is a critical determinant of these interactions in mammalian cells and determine X-ray crystal structures that show the molecular basis of SPOP associations with these proteins. These studies reveal a new consensus sequence for substrate-binding to SPOP that is necessary for substrate ubiquitylation, thus expanding the sequence rules required for SPOP-mediated E3 ligase substrate recognition.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trypanosomatid histones: the building blocks of the epigenetic code of highly divergent eukaryotes. 锥虫组蛋白：高度分化的真核生物表观遗传密码的组成部分。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-03-14 DOI: 10.1042/BCJ20240543

Josefina Ocampo, Santiago Carena, María Del Rosario López, Valentina Sol Vela, Romina Trinidad Zambrano Siri, Sofia Antonella Balestra, Guillermo Daniel Alonso

{"title":"Trypanosomatid histones: the building blocks of the epigenetic code of highly divergent eukaryotes.","authors":"Josefina Ocampo, Santiago Carena, María Del Rosario López, Valentina Sol Vela, Romina Trinidad Zambrano Siri, Sofia Antonella Balestra, Guillermo Daniel Alonso","doi":"10.1042/BCJ20240543","DOIUrl":"https://doi.org/10.1042/BCJ20240543","url":null,"abstract":"Histones play a fundamental role in eukaryotic organisms not only as scaffolding proteins in DNA packaging but also in regulating gene expression. They constitute the protein reel around which DNA wraps forming nucleosomes. This initial packing gives rise to the chromatin fiber which is next folded into three-dimensional arrangements. Additionally, histones have expanded their functions through the emergence of histone variants which have specialized purposes and can deeply affect chromatin organization and dynamics. Moreover, both canonical histones and histone variants comprise the building blocks of the histone code by being targets of different post-translational modifications (PTMs) that occur in a highly regulated manner both in place and time. Most of the above-mentioned about chromatin organization is conserved among eukaryotes. However, trypanosomatid histones have many peculiarities that entail a special description. In this review, we compile the current knowledge of canonical core histones, histone variants, and their PTMs in trypanosomatids. We highlight the similarities and differences between histone variants and their canonical counterparts in trypanosomatids, and we compare them with those from model organisms. Finally, we discuss the crosstalk between different histone marks and their genomic distribution underlying the uniqueness of trypanosomatids.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0