A substantial portion of the proteome consists of intrinsically disordered regions (IDRs) that do not fold into well-defined structures. IDRs often comprise low-complexity domains (LCDs), whose repetitive, compositionally biased sequences drive multivalent interactions that can lead to liquid-liquid phase separation, forming biomolecular assemblies. These LCD-mediated assemblies play an important role in transcriptional control, and productive output depends not on their mere presence but on how strongly and selectively LCDs interact. The present review integrates the optimal-interaction, or 'Goldilocks,' principle with RNA polymerase II phosphorylation and RNA-mediated feedback into a unified mechanistic framework spanning the transcription cycle. We connect dysregulation of LCD-mediated multivalent interactions to pathological transcription in cancer, neurodegeneration, and developmental disorders, whether through oncogenic LCD fusions, disease-associated post-translational modifications, or mutations altering phase-separation propensity. We further summarize experimental approaches for studying LCD function, discuss current methodological limitations, and highlight directions for future research.

Many viruses manipulate the host cell cycle to enhance viral replication and promote their evasion of host immune defenses. Human immunodeficiency virus type 1 (HIV-1) is no exception and triggers cell cycle arrest during its infection of replicating CD4+ T cells, acting predominantly through the activities of the viral proteins Vpr and Vif. Here, we summarize HIV-1's effects on cell cycle regulation, focusing on the distinct mechanisms that underpin Vpr and Vif's modulation of cell cycle checkpoints. We also discuss how these activities, when combined, may help the virus to enhance replication and promote reactivation from long-term latency-the major barrier to a cure for HIV/AIDS. A deeper understanding of how HIV-1 remodels the host cell cycle should reveal important new cell biology and may inform the development of therapeutic strategies relevant to curative interventions.

Photosystem II is a highly conserved protein complex found across all oxygenic phototrophs and the source of almost all biologically available electrons and atmospheric oxygen. This large, membrane-bound complex is at continuous risk of damage under direct, full sunlight, and those organisms that live under such conditions have developed photoprotective mechanisms to address this stressor. One such mechanism, photosystem II-cyclic electron flow (PSII-CEF), is a poorly understood pathway by which charge-separated electrons are recombined with holes after an extended separation and multiple electron transfer events. This mechanism is critical to the survival of the fastest-growing known eukaryotic phototrophs, playing a critical role in both native extremophiles and lab-adapted strains. However, the path electrons take during this recombinative process is not known. In the present review, we address the state of the field and the challenges facing implementation of PSII-CEF as a component of photosynthetic organism protection, survival, and improved growth.

Cellular plasticity is a central feature of malignant progression, allowing tumour cells to change identity during tumour evolution, therapeutic adaptation, and metastatic dissemination. This issue is especially acute in lung cancer, where the respiratory epithelium is intrinsically permissive to cell-state change. Genetic lesions, chromatin regulation, and metabolic adaptation are often framed as parallel determinants of lineage plasticity. Emerging evidence instead points to functional coupling across these layers. Oncogenic alterations can weaken lineage fidelity and open alternative trajectories, chromatin regulators can stabilise transitional states and enforce new transcriptional programmes, and metabolic rewiring can supply the biochemical conditions required for these states to emerge and persist. Microenvironmental cues further influence which trajectories are selected and maintained. Here, we discuss the genetic, epigenetic, and metabolic determinants of lineage plasticity in lung cancer, focusing on the points at which they intersect. We propose that plasticity is most usefully understood as a coupled regulatory state, arising from the interaction between oncogenic context, chromatin control, and metabolic support. Defining how these dependencies arise and become functionally coupled within high-plasticity transitional states should help identify points at which lineage switching can be intercepted before alternative lineage programmes are stabilised.

The p38γ and p38δ mitogen-activated protein kinases (MAPKs) are members of the p38 family that have emerged as important regulators of inflammatory signaling. Initially considered minor or alternative isoforms, accumulating evidence has revealed distinct and overlapping functions for p38γ and p38δ in innate immunity, tissue homeostasis, inflammatory disease, and cancer. These kinases regulate immune responses through diverse mechanisms controlling cytokine production, gene expression, immune-cell activation, and migration. In addition, recent studies suggest that some functions of p38γ and p38δ may occur independently of their catalytic activity, highlighting the complexity of their biological roles. The present review summarizes current knowledge of the molecular features, substrates, immune cell functions, and disease associations of p38γ and p38δ and discusses their potential as therapeutic targets while addressing the challenges associated with their pharmacological modulation.

P4-ATPases establish and maintain transbilayer lipid asymmetry in eukaryotic membranes by transporting phospholipids from the exoplasmic to the cytosolic membrane leaflet at the expense of ATP hydrolysis. In recent years, biochemical analysis together with an increasing number of cryo-electron microscopy structures has substantially increased our understanding of the lipid transport cycle and substrate recognition by P4-ATPases. However, the underlying molecular mechanism governing P4-ATPase activation and regulation remains less well understood. The present review aims to summarize current insights into the molecular mechanisms controlling P4-ATPase activation and regulation. We discuss autoinhibition by N- and C-terminal extensions, activation by regulatory lipids, particularly phosphoinositides, regulation by interacting proteins including small GTPases and guanine nucleotide exchange factors, and post-translational modifications, especially phosphorylation. Together, these studies reveal that P4-ATPase activity is controlled by a complex and multilayered regulatory network that enables precise control of lipid transport. Future studies combining structural, biochemical, and cellular approaches will be essential to elucidate how these mechanisms cooperate to maintain membrane lipid homeostasis and support diverse cellular functions.

Folates are essential metabolites of the cell and need to be acquired either by transport or biosynthesis. All metazoa including humans, some bacteria, and some protozoa acquire it solely through specific transporters. Plants and fungi, in contrast, have the capacity both for de novo biosynthesis and for uptake through plasma membrane folate transporters. These recently identified transporters belong to the oligopeptide transporter (OPT) family. Folate transporters from this family have been identified in yeasts and other fungi, including pathogenic fungi. They have also been observed in plants such as Arabidopsis thaliana and have the ability to transport both synthetic and natural folates including the naturally abundant 5-methyl tetrahydrofolate. In Saccharomyces cerevisiae, the folate transporter Opt1p (Hgt1p) is a proton-coupled transporter that was already known to transport glutathione (GSH). While in some organisms a single transporter is able to transport both substrates, in other organisms separate transporters in this family exist for folate and GSH. Mutational, kinetic, and functional studies of S. cerevisiae Opt1p have identified residues involved in substrate translocation, including those specific for folate or GSH recognition, as well as for proton-coupled transport. These studies suggest, in analogy to a human proton-coupled folate transporter and a plant OPT family phytosiderophore transporter, HvYS1, that proton-driven folate transport follows an alternating access mechanism with features described here. These transporters have implications for drug development strategies targeting the folate pathway of fungi and have importance in folate biofortification strategies for crops.

Innate immune signalling is uniquely driven through the formation of supramolecular organising centres (SMOCs), which couple receptor activation with downstream effector recruitment. The adaptor protein TRIF coordinates interferon, inflammatory, and cell death responses downstream of TLR3 and TLR4 activation, yet exactly how this protein drives such diverse outputs remains unresolved. Recent structural studies of recombinant TRIF, alongside single-molecule fluorescence imaging of endogenously expressed TRIF in live cells, reveal that TRIF assembles into complexes with heterogeneous size and morphology, with monomeric and low-order complexes associated with early-phase interferon signalling and mature, RIPK1-containing complexes associated with NF-κB activation. This review explores how differences in the structural architecture of the TRIFosome, from TIR-mediated oligomerisation through to RHIM-mediated cross-linking, may underlie this divergence in signalling outcome. Finally, this review discusses the translational opportunities that coordinating scaffold assembly with downstream function presents, including structure-selective therapeutics capable of shifting the balance between TRIF's signalling outputs and novel diagnostics that could be built on TRIFosome heterogeneity as a molecular fingerprint of disease.

We highlight the multifunctionality of the Hel308 and HELQ Ski2-like 'helicases' as they toggle between DNA annealing and DNA translocation across multiple DNA repair pathways. Defects in Hel308/HELQ cause genetic instability, including dysregulated homologous recombination. New data reveal how Hel308 and HELQ switch between DNA translocation and annealing, a mechanism that may restrain recombination to short tracts by curbing extensive DNA synthesis. We describe a PWI-like innovation in HELQ that evolved in bilaterian animals-absent from other animals and archaea-which we propose is an ATR-targeted phosphoregulatory module, coordinating protein interactions and, through those, DNA repair-recombination reactions. The overall picture is of Hel308 and HELQ as ancient DNA annealing enzymes, aided by short bursts of ATP-powered DNA translocation, kept in balance by molecular switches and the additional regulatory surfaces that arose in some animals.

The nuclear envelope (NE) establishes an essential physical separation between the nucleoplasm and cytoplasm in eukaryotic cells. Its structural integrity ensures selective molecular exchange through nuclear pores, a fundamental feature of eukaryotic cells. For this reason, it has long been assumed that the NE remains intact. However, recent studies revealed localized rupture of the NE in diverse physiological and pathological contexts. These ruptures can be resealed by endogenous mechanisms, suggesting that rupture-resealing dynamics contribute to homeostasis and are altered in disease. In the present review, we summarize physiological and pathological contexts in which NE rupture has been observed. We evaluate major hypotheses regarding its causes and consequences and discuss current understanding of the mechanisms and regulation of NE resealing. We conclude by highlighting key knowledge gaps in the pathophysiological roles of NE rupture and resealing.

Rhinovirus (RV) infection is responsible for the majority of cases of viral exacerbations of asthma. Understanding the cellular and molecular mechanisms that cause asthma exacerbations is an absolute requirement for the development of effective treatments. Emerging literature suggests that cell death may have an important role in RV-induced exacerbations. Several types of programmed cell death (PCD) have been implicated in asthma, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Increased presence of apoptotic airway epithelial cells in the sputum of adult and paediatric asthma patients is suggestive of defects in apoptosis. Elevated levels of phosphorylated mixed lineage kinase domain-like protein and receptor-interacting serine/threonine-protein kinase 3, markers of active necroptosis, have been found in the serum of asthmatic patients. Gasdermin B, a member of the gasdermin family of pyroptosis executioner proteins, has a strong genetic linkage to severe asthma. Expression level of GSDMB correlated with asthma exacerbations and antiviral pathways. Lipid peroxidation and increased airway iron levels, both suggestive of ferroptosis, have been observed in asthma patients. RV infection of epithelial cells triggers an inflammatory response, which can provide the necessary pro-inflammatory chemokines and cytokines to initiate PCD, such as tumour necrosis factor-α. RV exploits PCD such as apoptosis, necroptosis, pyroptosis, and ferroptosis to aid its replication and release, while modulating them probably to limit immune response. In the present review, we investigate the concept that pro-inflammatory PCD pathways modulated by RV infection in the context of asthma lead to prolonged inflammatory and immune responses that are key to asthma exacerbations.

Wheat (Triticum aestivum) is a cornerstone of global food security, yet its productivity is threatened by fungal pathogens such as Fusarium graminearum, Zymoseptoria tritici, and Rhizoctonia solani. These pathogens not only reduce yield but can also compromise grain quality and food safety through the production of mycotoxins. Traditional control strategies, primarily reliant on chemical fungicides and resistant cultivars, face limitations due to evolving pathogen resistance, environmental concerns, and regulatory restrictions. In recent years, the plant microbiome has emerged as a promising frontier in sustainable crop protection. The wheat microbiome, encompassing microbial communities in the rhizosphere, endosphere (root and leaf), and phyllosphere, plays a pivotal role in plant health and resilience. These microbes can suppress fungal pathogens through diverse mechanisms, both directly and indirectly. This mini-review explores the antifungal potential of the wheat microbiome, highlighting key microbial taxa, mechanisms of action with a focus on the underlying biochemistry and molecular processes, and recent advances in omics and microbiome-based biocontrol strategies. This extends to a case study on our own endophyte biocontrol and biochemistry discovery pipeline. We detail the impacts of fungal pathogen exposure and farming practices on wheat microbiome composition and phytopathogen-suppressive traits and highlight pathways for harnessing microbial communities to enhance wheat resistance.

Interferon regulatory factor 5 (IRF5) is a transcription factor at the nexus of immune regulation, inflammation, and autoimmune disease. Studies have shown that dysregulation of IRF5 is strongly implicated in the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease. While originally described as a regulator downstream of Toll-like receptor (TLR)-MyD88 signaling in myeloid cells, further studies demonstrate a more complex role for IRF5 in mediating adaptive immune responses as well. In this review, we provide a summary of the role of IRF5 across the major immune cell populations in which it is expressed. We discuss the mechanistic basis of IRF5 function in each population, highlight shared themes, and examine the evidence supporting IRF5 as a promising therapeutic target whose inhibition may selectively dampen pathological inflammation while preserving protective immunity. We thus provide an overview of how IRF5 bridges both innate and adaptive immune responses.

Extracellular electron transfer (EET) is a central process in the respiratory metabolism of electrogenic bacteria, enabling cells to exchange electrons with extracellular acceptors and donors. This capability has opened opportunities to exploit these bacteria in diverse practical applications, many of which would benefit from a precise understanding of the electron transfer (ET) events occurring within their respiratory chains. These chains rely on highly populated networks of c-type cytochromes that mediate electron flow across cellular compartments toward terminal electron acceptors. Although genomic, proteomic, biochemical, and structural studies have identified many ET components, defining their physiological redox partners and the directionality of electron flow remains challenging. This difficulty arises from the similar spectroscopic properties of key cytochromes, their transient interactions, and the complex overlap of their redox potential windows. In the present review, we examine how recently developed NMR-based strategies have been used to identify redox complexes established between cytochromes located in the inner membrane, periplasm, outer membrane, and extracellular conductive structures in the bacterium Geobacter sulfurreducens. These strategies exploited the distinct redox-dependent NMR fingerprints of individual heme groups, allowing direct detection of electron exchange, redox equilibria, and transient protein-protein interactions. Collectively, these studies reveal that ET pathways are not organized as single linear chains, but rather as dynamic and highly interconnected redox networks characterized by weak transient redox complexes and extensive promiscuity. This organization provides bacterial electron-buffering capacity, functional flexibility, and adaptability to changing environmental redox conditions.

Peroxisomes are dynamic organelles with diverse metabolic functions that are essential for life in plants and mammals. In humans, peroxisomal defects underlie peroxisome biogenesis disorders, which are often fatal. In plants, peroxisomes contribute to photorespiration and phytohormone production during plant development and are the sole site of fatty acid β-oxidation, which is critical for fat mobilization during germination. Despite their functional diversity, much of the machinery involved in building and maintaining peroxisomes is conserved across most eukaryotes. The model plant Arabidopsis thaliana is ideal for peroxisome studies due to its large peroxisomes, whole-organism and molecular assays for peroxisome function, and facile genetics. New applications of microscopy, computational modeling, and biochemistry have advanced the understanding of peroxisome biogenesis across eukaryotic life. These advances have generated insights into the functions of the proteins involved in peroxisome biogenesis, known as peroxins. Here, we review knowledge of Arabidopsis thaliana peroxins and discuss how new perspectives on peroxin functions across kingdoms inform future research on plant peroxisomes.