Biological ChemistryPub Date : 2025-04-23Print Date: 2025-03-26DOI: 10.1515/hsz-2024-0149
Liudy García-Hernández, Lingfeng Dai, Arielis Rodríguez-Ulloa, Ying Yi, Luis J González, Vladimir Besada, Wen Li, Silvio E Perea, Yasser Perera
{"title":"Time- and dose-dependent effects of CIGB-300 on the proteome of lung squamous cell carcinoma.","authors":"Liudy García-Hernández, Lingfeng Dai, Arielis Rodríguez-Ulloa, Ying Yi, Luis J González, Vladimir Besada, Wen Li, Silvio E Perea, Yasser Perera","doi":"10.1515/hsz-2024-0149","DOIUrl":"10.1515/hsz-2024-0149","url":null,"abstract":"<p><p>Proteome-wide scale in a dose- and time-depending setting is crucial to fully understand the pharmacological mechanism of anticancer drugs as well as identification of candidates for drug response biomarkers. Here, we investigated the effect of the CIGB-300 anticancer peptide at IC<sub>50</sub> and IC<sub>80</sub> doses during 1 and 4 h of treatment on the squamous lung cancer cell (NCI-H226) proteome. An overwhelming dose-dependent inhibitory effect with minor up-regulated proteins was observed by increasing CIGB-300 dose level. Functional enrichment was also CIGB-300 dose-dependent with common or exclusively regulated proteins in each dose and time settings. A protein core involving small molecule biosynthesis, aldehyde metabolism and metabolism of nucleobases was regulated irrespectively to the dose or the treatment time. Importantly, a group of proteins linked to NSCLC tumor biology, poor clinical outcome and some Protein Kinase CK2 substrates, were significantly regulated by treating with both CIGB-300 doses. Likewise, we observed a consistent downregulation of different proteins that had been already reported to be inhibited by CIGB-300 in lung adenocarcinoma and acute myeloid leukemia. Overall, our proteomics-guided strategy based on time and drug dose served to uncover novel clues supporting the CIGB-300 cytotoxic effect and also to identify putative pharmacodynamic biomarkers in NSCLC.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":"89-100"},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The mitochondrial unfolded protein response: acting near and far.","authors":"Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe","doi":"10.1515/hsz-2025-0107","DOIUrl":"https://doi.org/10.1515/hsz-2025-0107","url":null,"abstract":"<p><p>Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPR<sup>mt</sup> is activated. The UPR<sup>mt</sup> ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPR<sup>mt</sup> not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPR<sup>mt</sup> in the invertebrate model organism <i>Caenorhabditis elegans</i> and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPR<sup>mt</sup> in worms, flies and mice, and how UPR<sup>mt</sup> activation in specific tissues affects organismal metabolism and longevity.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Back to the basics: the molecular blueprint of plant heat stress transcription factors.","authors":"Sotirios Fragkostefanakis, Enrico Schleiff, Klaus-Dieter Scharf","doi":"10.1515/hsz-2025-0115","DOIUrl":"https://doi.org/10.1515/hsz-2025-0115","url":null,"abstract":"<p><p>Heat stress transcription factors (HSFs) play a pivotal role in regulating plant responses to heat and other environmental stresses, as well as developmental processes. HSFs possess conserved domains responsible for DNA binding, oligomerization, and transcriptional regulation, which collectively enable precise and dynamic control of cellular responses to environmental stimuli. Functional diversification of HSFs has been demonstrated through genetic studies in model plants such as <i>Arabidopsis thaliana</i> and economically important crops like tomato, rice, and wheat. However, the underlying molecular mechanisms that govern HSF function remain only partially understood, and for a handful of HSFs. Advancements in structural biology, biochemistry, molecular biology, and genomics shed light into how HSFs mediate stress responses at the molecular level. These insights offer exciting opportunities to leverage HSF biology for gene editing and crop improvement, enabling the customization of stress tolerance traits via regulation of HSF-dependent regulatory networks to enhance thermotolerance. This review synthesizes current knowledge on HSF structure and function, providing a perspective on their roles in plant adaptation to a changing climate.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The proteostasis burden of aneuploidy.","authors":"Prince Saforo Amponsah, Zuzana Storchová","doi":"10.1515/hsz-2024-0163","DOIUrl":"https://doi.org/10.1515/hsz-2024-0163","url":null,"abstract":"<p><p>Aneuploidy refers to chromosome number abnormality that is not an exact multiple of the haploid chromosome set. Aneuploidy has largely negative consequences in cells and organisms, manifested as so-called aneuploidy-associated stresses. A major consequence of aneuploidy is proteotoxic stress due to abnormal protein expression from imbalanced chromosome numbers. Recent advances have improved our understanding of the nature of the proteostasis imbalance caused by aneuploidy and highlighted their relevance with respect to organellar homeostasis, dosage compensation, or mechanisms employed by cells to mitigate the detrimental stress. In this review, we highlight the recent findings and outline questions to be addressed in future research.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biological ChemistryPub Date : 2025-04-14Print Date: 2025-03-26DOI: 10.1515/hsz-2024-0157
Christian Werner, Sophia Eimermacher, Hugo Harasimowicz, Dietmar Fischer, Markus Pietsch, Karsten Niefind
{"title":"A CK2α' mutant indicating why CK2α and CK2α', the isoforms of the catalytic subunit of human protein kinase CK2, deviate in affinity to CK2β.","authors":"Christian Werner, Sophia Eimermacher, Hugo Harasimowicz, Dietmar Fischer, Markus Pietsch, Karsten Niefind","doi":"10.1515/hsz-2024-0157","DOIUrl":"10.1515/hsz-2024-0157","url":null,"abstract":"<p><p>Protein kinase CK2 (casein kinase 2) mainly exists as heterotetrameric holoenzyme with two catalytic subunits (CK2α or CK2α') bound to a homodimer of non-catalytic subunits (CK2β). With <i>CSNK2A1</i> and <i>CSNK2A2</i>, the human genome contains two paralogs encoding catalytic CK2 subunits. Both gene products, called CK2α and CK2α', strongly interact with CK2β. An earlier report that CK2α' has a lower CK2β affinity than CK2α is confirmed via isothermal titration calorimetry in this study. Furthermore, we show with a fluorescence-anisotropy assay that a CK2β-competitive peptide binds less strongly to CK2α' than to CK2α. The reason for the reduced affinity of CK2α' to CK2β and CK2β competitors is puzzling: both isoenzymes have identical amino acid compositions at their CK2β interfaces, but the β4β5 loop, a component of this interface, is conformationally less adaptable in CK2α' than in CK2α due to intramolecular constraints. To release these constraints, we constructed a CK2α' mutant that was equalized to CK2α at the backside of the β4β5 loop. Concerning thermostability, affinity to CK2β or CK2β competitors and 3D-structure next to the β4β5 loop, this CK2α' mutant is more similar to CK2α than to its own wild-type, suggesting a critical role of the β4β5 loop adaptability for CK2β affinity.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":"101-115"},"PeriodicalIF":2.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The nascent polypeptide-associated complex (NAC) as regulatory hub on ribosomes.","authors":"Laurenz Rabl, Elke Deuerling","doi":"10.1515/hsz-2025-0114","DOIUrl":"https://doi.org/10.1515/hsz-2025-0114","url":null,"abstract":"<p><p>The correct synthesis of new proteins is essential for maintaining a functional proteome and cell viability. This process is tightly regulated, with ribosomes and associated protein biogenesis factors ensuring proper protein production, modification, and targeting. In eukaryotes, the conserved nascent polypeptide-associated complex (NAC) plays a central role in coordinating early protein processing by regulating the ribosome access of multiple protein biogenesis factors. NAC recruits modifying enzymes to the ribosomal exit site to process the N-terminus of nascent proteins and directs secretory proteins into the SRP-mediated targeting pathway. In this review we will focus on these pathways, which are critical for proper protein production, and summarize recent advances in understanding the cotranslational functions and mechanisms of NAC in higher eukaryotes.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Unclogging of the TOM complex under import stress.","authors":"Joshua Jackson, Thomas Becker","doi":"10.1515/hsz-2025-0110","DOIUrl":"https://doi.org/10.1515/hsz-2025-0110","url":null,"abstract":"<p><p>Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biological ChemistryPub Date : 2025-03-24Print Date: 2025-03-26DOI: 10.1515/hsz-2024-0160
Christelle Marminon, Christian Werner, Alexander Gast, Lars Herfindal, Johana Charles, Dirk Lindenblatt, Dagmar Aichele, Angélique Mularoni, Stein Ove Døskeland, Joachim Jose, Karsten Niefind, Marc Le Borgne
{"title":"Exploring the biological potential of the brominated indenoindole MC11 and its interaction with protein kinase CK2.","authors":"Christelle Marminon, Christian Werner, Alexander Gast, Lars Herfindal, Johana Charles, Dirk Lindenblatt, Dagmar Aichele, Angélique Mularoni, Stein Ove Døskeland, Joachim Jose, Karsten Niefind, Marc Le Borgne","doi":"10.1515/hsz-2024-0160","DOIUrl":"10.1515/hsz-2024-0160","url":null,"abstract":"<p><p>Protein kinase CK2 is a promising therapeutic target, especially in oncology. Over the years, various inhibitors have been developed, with polyhalogenated scaffolds emerging as a particularly effective class. Halogens like bromine and chlorine enhance inhibitor stability by forming additional interactions within the ATP pocket. Among halogenated scaffolds, benzotriazole and benzimidazole have led to potent molecules such as 4,5,6,7-tetrabromo-1<i>H</i>-benzotriazole (IC<sub>50</sub> = 300 nM) and 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (IC<sub>50</sub> = 140 nM). Modifications, including 4,5,6-tribromo-7-ethyl-1<i>H</i>-benzotriazole (IC<sub>50</sub> = 160 nM), further improved activity. Changing scaffolds while retaining halogens has enabled design of new inhibitors. Flavonols, dibenzofuranones, and the indeno[1,2-<i>b</i>]indole scaffold are key examples. Halogenation of the reference molecule 5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione (<b>4b</b>, IC<sub>50</sub> = 360 nM) significantly boosted potency. The study focused on introducing four halogens, yielding to the compound 1,2,3,4-tetrabromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione (<b>MC11</b>), with an IC<sub>50</sub> of 16 nM. Co-crystallography revealed how bromine atoms enhance binding, and <b>MC11</b> demonstrated strong <i>in cellulo</i> activity, particularly against leukemic cell lines like IPC-Bcl2.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":"125-138"},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biological ChemistryPub Date : 2025-03-17Print Date: 2025-01-29DOI: 10.1515/hsz-2024-0135
Joseph G Lundgren, Michael G Flynn, Karin List
{"title":"GPI-anchored serine proteases: essential roles in development, homeostasis, and disease.","authors":"Joseph G Lundgren, Michael G Flynn, Karin List","doi":"10.1515/hsz-2024-0135","DOIUrl":"10.1515/hsz-2024-0135","url":null,"abstract":"<p><p>The glycosylphosphatidylinositol (GPI)-anchored serine proteases, prostasin and testisin, have essential roles in diverse physiological functions including development, reproduction, homeostasis and barrier function of epithelia, angiogenesis, coagulation, and fibrinolysis. Important functions in pathological conditions such as cancer, kidney disease and cardiovascular disease have also been reported. In this review, we summarize current knowledge of the cellular and <i>in vivo</i> roles of prostasin and testisin in physiology and pathophysiology and explore the underlying molecular mechanisms. We discuss how new insights of their role in cancer and cardiovascular disease may facilitate translation into clinical settings in the future.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":"1-28"},"PeriodicalIF":2.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Unfolded protein responses in <i>Chlamydomonas reinhardtii</i>.","authors":"Sarah Gabelmann, Michael Schroda","doi":"10.1515/hsz-2025-0101","DOIUrl":"https://doi.org/10.1515/hsz-2025-0101","url":null,"abstract":"<p><p>The disruption of protein homeostasis leads to the increased un- and misfolding of proteins and the formation of toxic protein aggregates. Their accumulation triggers an unfolded protein response that is characterized by the transcriptional upregulation of molecular chaperones and proteases, and aims to restore proteome integrity, maintain cellular function, suppress the cause of perturbation, and prevent disease and death. In the green microalga <i>Chlamydomonas reinhardtii</i>, the study of this response to proteotoxic stress has provided insights into the function of chaperone and protease systems, which are, though simpler, closely related to those found in land plants. In addition, there has been considerable progress in understanding the triggers and regulation of compartment-specific unfolded protein responses. This review provides an overview on how the dysfunction of protein homeostasis is sensed in the different compartments of <i>Chlamydomonas</i>, and summarizes the current knowledge on the pathways that are triggered to restore equilibrium in the cell, while also highlighting similarities and differences to the unfolded protein responses of other model organisms.</p>","PeriodicalId":8885,"journal":{"name":"Biological Chemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}