{"title":"Ubiquitin beyond the proteome: lipids, glycans, metabolites, nucleic acids, and an expanding molecular landscape.","authors":"Akinori Endo, Yukiko Yoshida","doi":"10.1042/BST20260081","DOIUrl":"10.1042/BST20260081","url":null,"abstract":"<p><p>Ubiquitination is a versatile post-translational modification process in which the small globular protein ubiquitin is covalently attached to substrate proteins to generate diverse cellular signals. Although originally characterized by its role in proteasome-mediated protein degradation, ubiquitination is now recognized as a central regulator of numerous processes, including signaling, trafficking, and immunity. Canonical ubiquitination is mediated by a cascade of E1 (activating), E2 (conjugating), and E3 (ligase) enzymes that repeatedly conjugate ubiquitin molecules to lysine residues on substrate proteins, leading to the formation of polyubiquitin chains with distinct topologies. The modification is reversed by deubiquitinating enzymes. Notably, components of the ubiquitin system comprise approximately 7% of the human proteome, underscoring its importance in biological regulation. Recent advances have revealed the broad scope of ubiquitination. Ubiquitin was found to conjugate not only to lysine but also to serine, threonine, and cysteine, indicating its unexpected chemical flexibility. Furthermore, ubiquitination can be directed toward other post-translational modifications, particularly glycosylation and ADP-ribosylation, highlighting the extensive crosstalk between modification systems. Strikingly, lipids, sugars, metabolites, nucleic acids, and even synthetic small-molecule compounds have been identified as ubiquitinated substrates. The hypothesis that virtually all classes of molecules are targeted by ubiquitination has become increasingly plausible. Taken together, these findings redefine ubiquitination as a far more general modification process than previously appreciated. In this mini-review, we focus on recent progress in non-proteinaceous ubiquitination research, summarize emerging substrate classes, and discuss key challenges in elucidating the underlying mechanisms and physiological roles of this expanding modification landscape.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"745-754"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13270118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xin Zhang, Christopher Luo, Kevin Coughlin, Feng-Qian Li, Ken-Ichi Takemaru, Ledong Wan
{"title":"Transcriptomic regulation of pancreatic acinar cell homeostasis and plasticity.","authors":"Xin Zhang, Christopher Luo, Kevin Coughlin, Feng-Qian Li, Ken-Ichi Takemaru, Ledong Wan","doi":"10.1042/BST20253124","DOIUrl":"10.1042/BST20253124","url":null,"abstract":"<p><p>Pancreatic acinar cells are highly specialized secretory epithelial cells in which coordinated transcriptional, epigenetic, and post-transcriptional regulatory mechanisms maintain digestive enzyme production, polarized architecture, and lineage fidelity. This homeostatic network preserves acinar identity while enabling rapid adaptation to physiological stress. Disruption of these regulatory mechanisms triggers acinar-to-ductal metaplasia (ADM), a reversible reprogramming state that supports acinar cell survival and regeneration after acute injury. However, if ADM persists under chronic inflammation or oncogenic KRAS activation, it can facilitate the initiation of pancreatic ductal adenocarcinoma. Elucidating these mechanisms offers opportunities to restore acinar cell homeostasis, reverse ADM, and prevent neoplastic transformation. In this review, we summarize current knowledge on the transcriptional, epigenetic, and post-transcriptional regulation of acinar cell homeostasis and plasticity, with emphasis on their roles in ADM.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"681-697"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emily C Park, Andrew P Thompson, James M Murphy, Lung-Yu Liang, Isabelle S Lucet
{"title":"The multifaceted roles of receptor tyrosine pseudokinases in cellular signalling.","authors":"Emily C Park, Andrew P Thompson, James M Murphy, Lung-Yu Liang, Isabelle S Lucet","doi":"10.1042/BST20260770","DOIUrl":"10.1042/BST20260770","url":null,"abstract":"<p><p>Receptor tyrosine pseudokinases comprise approximately 10% of the receptor tyrosine kinase family and lack phosphotransferase activity due to substitutions of essential catalytic residues within their kinase folds. This review critically examines the eight human receptor tyrosine pseudokinases: EphA10, EphB6, HER3, PTK7, ROR1, ROR2, RYK, and STYK1. By reconciling recent structural and functional data, we highlight the diverse non-catalytic mechanisms these pseudokinases employ in cellular communication. This comprehensive analysis provides insights into non-canonical signalling pathways and highlights potential for therapeutic opportunities in diseases associated with pseudokinase dysfunction.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"727-743"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13259870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristian Herrera-Cid, Oskar Kaaber Thomsen, Linéa Désarbre, Rylee Blair Marin, Canan Doganli, Lotte Bang Pedersen, Lars Allan Larsen, Søren Tvorup Christensen
{"title":"The primary cilium at the helm: gatekeeper of TGF-β superfamily signaling in development, homeostasis, and disease.","authors":"Cristian Herrera-Cid, Oskar Kaaber Thomsen, Linéa Désarbre, Rylee Blair Marin, Canan Doganli, Lotte Bang Pedersen, Lars Allan Larsen, Søren Tvorup Christensen","doi":"10.1042/BST20253108","DOIUrl":"10.1042/BST20253108","url":null,"abstract":"<p><p>The transforming growth factor-beta (TGF-β) superfamily is crucial for regulating cell proliferation, differentiation, migration, and tissue homeostasis, and plays a central role in embryonic development and function of tissues and organs. Dysregulation of these pathways contributes to a broad spectrum of diseases, including cancer, fibrosis, and developmental disorders. The present review explores how the primary cilium, a specialized signaling organelle, orchestrates TGF-β superfamily signaling, with a focus on emerging evidence of its role in heart and brain development, as well as in tissue homeostasis.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"665-680"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lipid traffic: an enigmatic alliance between ORPs and a TMEM16-like protein at membrane contact sites.","authors":"Alicia Fabbre, Guillaume Drin","doi":"10.1042/BST20250365","DOIUrl":"10.1042/BST20250365","url":null,"abstract":"<p><p>Lipid transfer proteins (LTPs) play a critical role in distributing lipids within eukaryotic cells. In yeast, Osh6 and Osh7, which belong to the oxysterol-binding protein-related protein family, transfer phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) in exchange for phosphatidylinositol 4-phosphate (PI(4)P). These proteins localize at ER-PM contact sites by associating with Ist2, an ER-resident TMEM16-like protein that bridges the ER and PM via a long intrinsically disordered region (IDR). Recent studies have shown that this association ensures accurate PS transfer by concentrating Osh6 and Osh7 at the ER-PM interface while preserving their ability to access both membranes. However, it remains unclear how these LTPs function when bound to the Ist2 IDR, whose length far exceeds the ER-PM distance at contact sites, and why they do not integrate both the tethering and the PS/PI(4)P exchange functions, like their human homologs. Additionally, it has been revealed that Ist2 can transfer lipids across the ER membrane via a scramblase activity. Yet, whether and why this activity is coupled to the PS/PI(4)P exchange activity of Osh6 and Osh7 remains unknown. The Ist2-Osh6/7 system emerges as a fascinating model that integrates tethering, scramblase, and lipid exchange functions. Future studies of this system are likely to provide important insights into how lipid transfer processes are coordinated at membrane contact sites.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"793-802"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yasmin Stone, Ethan Morgan, Yong-Han Su, Ching-Ying Kuo, Ting-Yu Lin
{"title":"The impact of psuedouridine modification on human tRNA.","authors":"Yasmin Stone, Ethan Morgan, Yong-Han Su, Ching-Ying Kuo, Ting-Yu Lin","doi":"10.1042/BST20250258","DOIUrl":"10.1042/BST20250258","url":null,"abstract":"<p><p>Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to produce mature and functional molecules. Pseudouridine (Ψ), a derivative of uridine, is an abundant RNA modification and occurs at multiple positions within tRNAs. These modified sites are highly conserved across organisms. Classical biochemical studies have established that Ψ stabilises RNA-RNA interactions, but structural characterisations and molecular dynamics simulations reveal that Ψ can locally remodel tRNA architecture in ways that are dictated by where it is within tRNAs. Advances in transcriptome-wide Ψ mapping have uncovered additional modified sites beyond those previously described, with several novel sites appearing to be regulated in a cellular context-dependent manner. Furthermore, dysregulated pseudouridylation has been implicated in conditions ranging from cancer to inherited genetic disorders. Together, these developments reframe our understanding of Ψ from a well-established RNA stabiliser to a modification with roles far more dynamic, context-dependent, and clinically relevant than previously appreciated. The present review summarises and discusses the up-to-date developments in the impacts of pseudouridylation on human tRNA biogenesis, tRNA functions, and human health. More mechanistic questions remain open and will require further investigation. As pseudouridylation can also happen in mRNA and rRNA, exploring the interplay between these RNAs will be crucial for fundamental biology and advancing Ψ applications in biotechnology and biomedical uses.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"755-767"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13270119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yafan Yu, Robert M Bauer, Rabab Mahdi, Kurt H Piepenbrink
{"title":"Insight into the relationship between type IV pilus function and biofilm formation.","authors":"Yafan Yu, Robert M Bauer, Rabab Mahdi, Kurt H Piepenbrink","doi":"10.1042/BST20250151","DOIUrl":"10.1042/BST20250151","url":null,"abstract":"<p><p>Type IV pili (T4P) are protein nanofibers that can be extended and retracted from the surfaces of many bacterial taxa. They are involved in many aspects of bacterial physiology that differ between bacterial species, including surface motility, DNA uptake, and host-cell adherence, but genetically and structurally distinct type IV pilus systems from distantly related bacterial species have also been found to promote the formation of bacterial biofilms. The molecular mechanisms underpinning the promotion of biofilm remain an area of active investigation and may be both manifold and variable between type IV pilus systems. Two areas of recent interest are interactions between T4P and extracellular DNA and the relationship between surface-adhered biofilms and suspended aggregates. In the present review, we critically discuss the current state of knowledge of type IV pilus function and how these structures may interact with other biomolecules to influence the formation of multicellular bacterial communities. We examine the evidence for how alterations in DNA-binding, pilus retraction, and pilus composition have downstream effects on the formation of bacterial biofilms.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"633-650"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Non-canonical subunit functions in multiprotein complexes: insights from the Mediator complex.","authors":"Alexis Verger, Didier Monté, Vincent Villeret","doi":"10.1042/BST20260729","DOIUrl":"10.1042/BST20260729","url":null,"abstract":"<p><p>The Mediator complex is a central regulator of RNA polymerase II transcription, integrating signals from transcription factors and coordinating pre-initiation complex assembly. Beyond this canonical role, numerous studies have implicated Mediator complex in diverse cellular processes, including RNA processing, DNA repair, and translational control. These observations raise a fundamental question: do such functions reflect an expansion of Mediator activity as a complex, or the emergence of specialized functions at the level of individual subunits? In this review, we examine the ability of Mediator subunits to function independently of their canonical context and discuss the mechanistic principles that enable subunit specialization within multiprotein assemblies.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 6","pages":"781-791"},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benudhara Pati, Nibedita Nandy, Birendra Kumar Bindhani, Naresh Chandra Bal
{"title":"Pro-inflammatory cytokine-driven molecular signaling in skeletal muscle during cancer cachexia.","authors":"Benudhara Pati, Nibedita Nandy, Birendra Kumar Bindhani, Naresh Chandra Bal","doi":"10.1042/BST20260486","DOIUrl":"10.1042/BST20260486","url":null,"abstract":"<p><p>Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of muscle and fat, commonly observed among patients with cancer. It is very distinct from other skeletal muscle wasting such as sarcopenia and malnutrition and is known to reduce cancer treatment effectiveness. Cachexia progression is driven by a combination of factors, including hormonal dysregulation, anorexia, tumor-derived catabolic factors (in cancer cachexia), and systemic or muscular inflammation, all of which worsen overall muscle health. In this review, we will probe the role of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-α, TGF-β, IL-1β, and IL-8, in driving the systemic inflammation and disruption of muscle metabolic homeostasis that support the development of cachexia. These cytokines may be produced from various organs, including the adipose depots that contribute to muscle wasting and metabolic dysfunction by disrupting the equilibrium between anabolic and catabolic processes. The ubiquitin-proteasome system, NF-κB, and JAK/STAT3 are important molecular pathways that mediate cytokine-induced catabolic signaling. The review further analyzes the context-dependent dual functions of these cytokines and the molecular mechanisms underlying the loss of their regulatory control during cancer progression. The limited success of current therapeutic approaches for cancer cachexia highlights the urgent need for evaluation of more targetable mechanisms for the treatments. Here, one of our main objectives is to probe whether suppression of pro-inflammatory cytokine signaling and activation of anti-inflammatory pathways can be utilized to modulate the tumor microenvironment, thereby countering cancer cachexia.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 5","pages":"547-559"},"PeriodicalIF":4.4,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13181344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Direct or indirect: the crucial role of N-palmitate in hedgehog signaling.","authors":"Janna Puschmann, Kay Grobe","doi":"10.1042/BST20260268","DOIUrl":"10.1042/BST20260268","url":null,"abstract":"<p><p>During development, cells use concentration gradients of soluble signaling molecules, called morphogens, to determine their position within tissues and adopt the correct identity. Hedgehog (Hh) morphogens are a key but also unusual example of gradient formation, because their diffusion away from their origin to direct growth and patterning is first prevented by their dual N- and C-terminal lipidation by palmitate and cholesterol. These lipids associate the Hhs with the plasma membrane of the cells that produce them. Later, however, both lipids participate in the spatiotemporal release of Hh by accessory proteins and maintain Hh biofunction in vivo, either directly or indirectly. The present study explores these two mechanistic possibilities, focusing on the central role of N-palmitate in Hh-regulated development in both vertebrates and invertebrates.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 5","pages":"535-545"},"PeriodicalIF":4.4,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13181345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}