FEBS Letters最新文献

Lys48-linked ubiquitin chains, regulating proteasomal protein degradation, are known to include cyclized forms. This cyclization hinders recognition by many downstream proteins by occluding the Ile44-centered patch. In contrast, the A20-like Znf domain of ZNF216 (a ubiquitin-binding protein, A20 Znf) is expected to bind to cyclic ubiquitin chains via constitutively solvent-exposed surfaces. However, the underlying interaction mechanism remains unclear. Here, our ITC and NMR experiments collectively showed that cyclization did not interfere with and even slightly enhance the molecular recognition of diubiquitin by A20 Znf. This effect is explained by the cyclization-induced repression of conformational dynamics in diubiquitin and an enlarged molecular interface in the complex. Thus, these results suggest that cyclic ubiquitin chains can be involved in regulation of ZNF216-dependent proteasomal protein degradation.

The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field of study. A key player in maintaining this delicate equilibrium is the cohesin complex, a molecular machine with multifaceted roles. This review presents an in-depth exploration of these intricate connections and their significant impact on various human diseases.

The FtsEX membrane complex constitutes an essential component of the ABC transporter superfamily, widely distributed among bacterial species. It governs peptidoglycan degradation for cell division, acting as a signal transmitter rather than a substrate transporter. Through the ATPase activity of FtsE, it facilitates signal transmission from the cytosol across the membrane to the periplasm, activating associated peptidoglycan hydrolases. This review concentrates on the latest structural advancements elucidating the architecture of the FtsEX complex and its interplay with lytic enzymes or regulatory counterparts. The revealed three-dimensional structures unveil a landscape wherein a precise array of intermolecular interactions, preserved across diverse bacterial species, afford meticulous spatial and temporal control over the cell division process.

Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward the physiological significance of molecular structures known as R-loops. These structures arise when an RNA strand invades into the DNA duplex, and their formation is involved in a wide range of regulatory functions affecting gene expression, DNA repair processes or cell homeostasis. The persistent presence of R-loops, if not effectively removed, contributes to genome instability, underscoring the significance of the factors responsible for their resolution and modification. In this review, we provide a comprehensive overview of how R-loop processing can drive either a beneficial or a harmful outcome. Additionally, we explore the potential for manipulating such structures to devise rationalized therapeutic strategies targeting the aberrant accumulation of R-loops.

Fatty acid amide hydrolase (FAAH) is a conserved hydrolase in eukaryotes with promiscuous activity toward a range of acylamide substrates. The native substrate repertoire for FAAH has just begun to be explored in plant systems outside the model Arabidopsis thaliana. Here, we used ex vivo lipidomics to identify potential endogenous substrates for Medicago truncatula FAAH1 (MtFAAH1). We incubated recombinant MtFAAH1 with lipid mixtures extracted from M. truncatula and resolved their profiles via gas chromatography–mass spectrometry (GC–MS). Data revealed that besides N-acylethanolamines (NAEs), sn-1 or sn-2 isomers of monoacylglycerols (MAGs) were substrates for MtFAAH1. Combined with in vitro and computational approaches, our data support both amidase and esterase activities for MtFAAH1. MAG-mediated hydrolysis via MtFAAH1 may be linked to biological roles that are yet to be discovered.

Transporters for organic cations (OCs) facilitate exchange of positively charged molecules through the plasma membrane. Substrates for these transporters encompass neurotransmitters, metabolic byproducts, drugs, and xenobiotics. Consequently, these transporters actively contribute to the regulation of neurotransmission, cellular penetration and elimination process for metabolic products, drugs, and xenobiotics. Therefore, these transporters have significant physiological, pharmacological, and toxicological implications. In cells of renal proximal tubules, the vectorial secretion pathways for OCs involve expression of organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) on basolateral and apical membrane domains, respectively. This review provides an overview of documented regulatory mechanisms governing OCTs and MATEs. Additionally, regulation of these transporters under various pathological conditions is summarized. The expression and functionality of OCTs and MATEs are subject to diverse pre- and post-translational modifications, providing insights into their regulation in various pathological conditions. Typically, in diseases, downregulation of transporter expression is observed, probably as a protective mechanism to prevent additional damage to kidney tissue. This regulation may be attributed to the intricate network of modifications these transporters undergo, shedding light on their dynamic responses in pathological contexts.

Aging is a multifactorial process occurring in a pathophysiological continuum which leads to organ and system functional loss. While aging is not a disease, its pathophysiological continuum predisposes to illness and multimorbidity clusters which share common biomolecular mechanisms—the pillars of aging. Brain aging and neurodegeneration share many hallmarks with other age-related diseases. The central nervous system is often the weakest link susceptible to the aging process and its deterioration, resulting in cognitive impairment and other symptoms; the aging process is associated with proteostasis collapse, stem cell exhaustion, repair mechanisms, altered brain nutrient sensing, endothelial changes, inflammation, oxidative distress, and energy unbalance, as well as other disturbances. These mechanisms are highly interwoven, and considerable research is aimed at their disentanglement and detection of their clinically relevant impact, particularly in order to identify pharmacological and non-pharmacological preventive and therapeutic strategies.

Mitochondrial biogenesis requires precise regulation of both mitochondrial-encoded and nuclear-encoded genes. Nuclear receptor Nur77 is known to regulate mitochondrial metabolism in macrophages and skeletal muscle. Here, we compared genome-wide Nur77 binding site and target gene expression in these two cell types, which revealed conserved regulation of mitochondrial genes and enrichment of motifs for the transcription factor Yin-Yang 1 (YY1). We show that Nur77 and YY1 interact, that YY1 increases Nur77 activity, and that their binding sites are co-enriched at mitochondrial ribosomal protein gene loci in macrophages. Nur77 and YY1 co-expression synergistically increases Mrpl1 expression as well as mitochondrial abundance and activity in macrophages but not skeletal muscle. As such, we identify a macrophage-specific Nur77-YY1 interaction that enhances mitochondrial metabolism.

Elevated oxidative stress, which threatens genome stability, has been detected in almost all types of cancers. Cells employ various DNA repair pathways to cope with DNA damage induced by oxidative stress. Recently, a lot of studies have provided insights into DNA damage response upon oxidative stress, specifically in the context of transcriptionally active genomes. Here, we summarize recent studies to help understand how the transcription is regulated upon DNA double strand breaks (DSB) and how DNA repair pathways are selectively activated at the damage sites coupling with transcription. The role of RNA molecules, especially R-loops and RNA modifications during the DNA repair process, is critical for protecting genome stability. This review provides an update on how cells protect transcribed genome loci via transcription-coupled repair pathways.

Microtubules are a major component of the cytoskeleton and can accumulate a plethora of modifications. The microtubule detyrosination cycle is one of these modifications; it involves the enzymatic removal of the C-terminal tyrosine of α-tubulin on assembled microtubules and the re-ligation of tyrosine on detyrosinated tubulin dimers. This modification cycle has been implicated in cardiac disease, neuronal development, and mitotic defects. The vasohibin and microtubule-associated tyrosine carboxypeptidase enzyme families are responsible for microtubule detyrosination. Their long-sought discovery allows to review and summarise differences and similarities between the two enzymes families and discuss how they interplay with other modifications and functions of the tubulin code.