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Keratins form intermediate filament networks that stabilize epithelial cells and many cancer cells. During cytokinesis, these filaments must be locally disassembled at the cleavage furrow to allow furrow ingression and cell separation. In this issue, Harmanda et al. demonstrate that Aurora B kinase directly phosphorylates Keratin 8 at multiple sites, with pS34-K8 being highly enriched specifically at the contractile ring and the midzone. Using in vitro kinase assays, mass spectrometry, phospho-specific antibodies, CRISPR Keratin 8 knockout, and non-phosphorylatable/phosphomimetic mutants, the authors show that Aurora B-mediated phosphorylation promotes keratin filaments disassembly at the furrow. Noticeably, Keratin 8 scaffolds Aurora B to the midzone, creating a positive feedback loop that is essential for cytokinesis in epithelial cancer cells. These data reveal a novel, spatially regulated mechanism linking Aurora B to intermediate filament dynamics and highlight potential therapeutic opportunities in carcinomas that overexpress Keratin 8.

C-reactive protein (CRP) plays a central role in innate immunity and serves as a key biomarker of inflammation. Despite its clinical importance, the structural basis of CRP interactions with antibodies remains poorly characterized. Using cryo-electron microscopy (cryo-EM), we resolved the structure of immune complexes formed between pentameric CRP and monoclonal immunoglobulin G (IgG) antibodies at up to 2.4 Å resolution. The complexes display a barrel-shaped architecture, with two CRP pentamers bridged by three to five antibodies. We built an atomic model of the CRP-antibody interface, identifying a binding site on the A-face of CRP mediated exclusively by hydrogen bonds, without salt-bridge formation. These findings provide structural insights into CRP-IgG recognition and offer a basis for the rational design of improved antibodies.

CML is primarily driven by the oncogenic BCR-ABL fusion kinase; however, tyrosine kinase inhibitor (TKI) resistance remains a significant clinical challenge. A study by Zang et al. identified USP8 as a critical mediator of this resistance. USP8, a deubiquitinase, stabilizes the stress-response regulator EIF2S1 (eIF2α) by removing K48-linked ubiquitin chains. This stabilization sustains PERK-EIF2S1-mediated unfolded protein response (UPR) signaling. The UPR suppresses general protein translation while promoting the expression of adaptive stress-response genes, allowing CML cells to survive TKI-induced stress. Consequently, targeting the USP8-EIF2S1 axis is proposed as a key therapeutic strategy to overcome resistance and enhance patient outcomes.

To celebrate the launch of our latest Focus Issue on molecular microbiology, we have chosen to highlight a few of our favourite microbiology articles from our recent archive. The papers discussed here showcase the power of fundamental discoveries in molecular microbiology for improving human health. Please join us in revisiting these excellent articles, and do let us know your favourites.

The landscape of modern medicine has been transformed by protein-based therapeutics, offering targeted treatments for complex disorders with remarkable specificity and efficacy. However, these biologics face significant limitations in clinical settings, including rapid clearance, vulnerability to enzymatic degradation, poor absorption across biological membranes and inefficient distribution within target tissues. Artificial lipidation provides an innovative solution to these challenges, by the deliberate attachment of lipid groups to proteins and peptide structures. This biomimetic approach harnesses principles observed in natural post-translational modifications to create therapeutics with superior pharmacological profiles. By strategically incorporating lipid moieties, researchers can significantly prolong circulation half-life through albumin binding, protect against proteolytic breakdown, facilitate cellular uptake, customize pharmacokinetic parameters and enhance tissue-specific targeting. This Review provides a comprehensive analysis of current lipidation technologies, contrasting covalent modification strategies with noncovalent complexation approaches. We examine the molecular mechanisms underlying the therapeutic benefits, survey successful clinical applications and explore emerging opportunities across diverse therapeutic areas. Through this analysis, we offer insights to guide rational design decisions for developing optimized lipidated biotherapeutics with enhanced clinical performance.

Tight junctions (TJs) between pulmonary vascular endothelial cells (ECs) constitute the physical barrier that impedes the metastasis of tumor cells. We previously reported that circulating microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive extracellular vesicles (LC3⁺ EVs) derived from primary breast tumors were essential for establishing the premetastatic niche. However, the roles of LC3⁺ EVs in inducing vascular permeability and promoting tumor metastasis are unclear. In this study, we revealed that the expression of occludin and tight junction protein 1 [also known as zona occludens protein 1 (ZO-1)], two major TJ proteins, could be reduced by circulating LC3⁺ EVs, which subsequently increased vascular permeability, facilitated the invasion of circulating tumor cells, and eventually resulted in increased lung metastasis. Heat shock protein 60 (HSP60) was identified as the key molecule on LC3⁺ EVs that induced the reduction of occludin and ZO-1 through the Toll-like receptor 2 (TLR2)-myeloid differentiation primary response protein MyD88 (MYD88)-Snail Family Transcriptional Repressor 1 (Snai1) signal cascade. Combined with our previous findings, these results demonstrate that removing circulating LC3⁺ EVs or targeting HSP60 on LC3⁺ EVs might be a promising way to prevent breast cancer lung metastasis.

Understanding the molecular basis of regulated nitrogen (N₂) fixation is essential for engineering N₂-fixing bacteria that fulfill the demand of crop plants for fixed nitrogen, reducing our reliance on synthetic nitrogen fertilizers. In Azotobacter vinelandii and many other members of Proteobacteria, the two-component system comprising the anti-activator protein (NifL) and the Nif-specific transcriptional activator (NifA)controls the expression of nif genes, encoding the nitrogen fixation machinery. The NifL-NifA system evolved the ability to integrate several environmental cues, such as oxygen, nitrogen, and carbon availability. The nitrogen fixation machinery is thereby only activated under strictly favorable conditions, enabling diazotrophs to thrive in competitive environments. While genetic and biochemical studies have enlightened our understanding of how NifL represses NifA, the molecular basis of NifA sequestration by NifL depends on structural information on their interaction. Here, we present mechanistic insights into how nitrogen fixation is regulated by combining biochemical and genetic approaches with a low-resolution cryo-electron microscopy (cryo-EM) map of the oxidized NifL-NifA complex. Our findings define the interaction surface between NifL and NifA and reveal how this interaction can be manipulated to generate bacterial strains with increased nitrogen fixation rates able to secrete surplus nitrogen outside the cell, a crucial step in engineering improved nitrogen delivery to crop plants.

Malaria is a severe disease that is transmitted by female Anopheles mosquitoes and caused by the Plasmodium parasite. Despite a decrease in mortality rate, it continues to pose significant challenges such as resistance to antimalarial drugs and insecticides, which necessitates the need for novel malaria control and elimination strategies. To identify new molecular targets for malaria control, there is a need to understand the molecular interaction between mosquitoes and parasites. Plasmodium ookinetes interact with the mosquito midgut proteins during midgut invasion and sporozoites interact with the mosquito salivary gland (SG) proteins. These interactions are crucial for the parasite's invasion of the mosquito midgut and SG, respectively. This review explores the involvement of various Plasmodium genes in male and female gametogenesis and parasite transmission, their interaction with the mosquito genes that facilitate parasite invasion, and how the mosquito immune system defends itself from the invading parasite. Understanding the biology underlying the interaction between mosquitoes and parasites may lead to a better comprehension of the disease and could help design efficient vector control strategies.

The FEBS Journal's Editorial Office is delighted to present our first Focus Issue of the year. In this Issue, we highlight some excellent research that advances the field of molecular microbiology. We welcome you to this celebration of all things bugs, drugs and 'biochem'. Read on to get a feel for the contents of this issue, then make sure to check out your favourites.

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2) is a crucial enzyme for synthesizing nicotinamide adenine dinucleotide (NAD) and plays a vital role in neuronal health. NMNAT2 mRNA levels correlate positively with cognitive function in older adults but decline after injuries or proteinopathies. In this study, we used chromosome conformation capture followed by high-throughput sequencing (4C-seq) to unbiasedly identify NMNAT2 regulatory regions throughout the human genome. Using various bioinformatics analyses with these genomic regions, referred to as interactomes, we identified NMNAT2-associated genes and putative transcription factors (TFs). NMNAT2 transcription increases in SH-SY5Y cells when they differentiate into a neuron-like state. Excitingly, our 4C-seq data revealed distinct sets of interactomes interacting with the NMNAT2 promoter in undifferentiated versus neuron-like SH-SY5Y cells. Using the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) snRNA-seq data, we showed that the expression levels of many NMNAT2-associated genes are significantly correlated with NMNAT2 transcription in human neurons. Our biological validation studies confirmed the requirement of two specific genomic regions and four TFs, including cyclic AMP-dependent transcription factor ATF4, cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6), transcription factor SOX11, and heat shock factor protein 1 (HSF1), in NMNAT2 transcription. ATF4 has been identified as an injury-responsive TF, whereas HSF1 is modulated by protein stress. Together, our study identifies distinctive genomic loci containing NMNAT2 regulatory elements in undifferentiated versus neuron-like SH-SY5Y cells, NMNAT2-associated genes, and putative NMNAT2-TFs.