FEBS Letters最新文献

Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.

The intricate mechanisms underlying transcription-dependent genome instability involve G-quadruplexes (G4) and R-loops. This perspective elucidates the potential link between these structures and genome instability in aging. The co-occurrence of G4 DNA and RNA-DNA hybrid structures (G-loop) underscores a complex interplay in genome regulation and instability. Here, we hypothesize that the age-related decline of sirtuin function leads to an increase in acetylated helicases that bind to G4 DNA and RNA-DNA hybrid structures, but are less efficient in resolving them. We propose that acetylated, less active, helicases induce persistent G-loop structures, promoting transcription-dependent genome instability in aging.

Neuronostatin suppresses the differentiation of white preadipocytes. However, the role of neuronostatin in brown adipose tissue remains elusive. Therefore, we investigated the impact of neuronostatin on the proliferation and differentiation of isolated rat brown preadipocytes. We report that neuronostatin and its receptor (GPR107) are synthesized in brown preadipocytes and brown adipose tissue. Furthermore, neuronostatin promotes the replication of brown preadipocytes via the AKT pathway. Notably, neuronostatin suppresses the expression of markers associated with brown adipogenesis (PGC-1α, PPARγ, PRDM16, and UCP1) and reduces cellular mitochondria content. Moreover, neuronostatin impedes the differentiation of preadipocytes by activating the JNK signaling pathway. These effects were not mimicked by somatostatin. Our results suggest that neuronostatin is involved in regulating brown adipogenesis.

Nanotechnology offers promising avenues for enhancing drug delivery systems, particularly in HIV-1 treatment. This study investigates a nanoemulsified formulation combining epigallocatechin gallate (EGCG) with dolutegravir (DTG) for managing HIV-1 infection. The combinatorial interaction between EGCG and DTG was explored through cellular, enzymatic, and molecular studies. In vitro assays demonstrated the potential of a dual drug-loaded nanoemulsion, NE-DTG-EGCG, in inhibiting HIV-1 replication, with EGCG serving as a supplementary treatment containing DTG. In silico molecular interaction studies highlighted EGCG's multifaceted inhibitory potential against HIV-1 integrase and reverse transcriptase enzymes. Further investigations are needed to validate the formulation's efficacy across diverse contexts. Overall, by integrating nanotechnology into drug delivery systems, this study represents a significant advancement in managing HIV-1 infection.

Alzheimer's disease (AD) involves reduced glutathione levels, causing oxidative stress and contributing to neuronal cell death. Our prior research identified diminished glutamate-cysteine ligase catalytic subunit (GCLC) as linked to cell death. However, the effect of GCLC on AD features such as amyloid and tau pathology remained unclear. To address this, we investigated amyloid pathology and tau pathology in mice by combining neuron-specific conditional GCLC knockout mice with amyloid precursor protein (App) knockin (KI) or microtubule-associated protein tau (MAPT) KI mice. Intriguingly, GCLC knockout resulted in an increased Aβ42/40 ratio. Additionally, GCLC deficiency in MAPT KI mice accelerated the oligomerization of tau through intermolecular disulfide bonds. These findings suggest that the decline in glutathione levels, due to aging or AD pathology, may contribute to the progression of AD.

Although scientists are generally motivated to adopt sustainable practices in their research, a lack of education is often limiting. Here, I aim to fill this gap by illustrating how to substantially reduce single-use plastic waste in scientific protocols. This article will outline the translation of the three fundamental principles of reduction, reuse, and miniaturization into experimental practice. The transfection of neurons in sterile conditions will be provided as a concrete example to discuss opportunities for change. Simply by reducing, miniaturizing, and reusing, a decrease in plastic waste of approximately 65% was achieved for exchangeable items. This article demonstrates the feasibility of adopting sustainable practices without compromising workflows or data quality.

Lipid droplets are ubiquitous organelles that can be formed by virtually all eukaryotic cells and fulfill central roles in lipid biology. They have a unique architecture that enables them to store variable amounts of neutral lipids such as triacylglycerol and sterol esters in a central hydrophobic core compartment, which is protected from the aqueous cytosol by an outer phospholipid monolayer. This monolayer houses the lipid droplet surface proteome that comprises a large number of lipid metabolism enzymes, which mediate key steps in the biosynthesis and turnover of membrane and storage lipids [[1]]. In recent years, lipid droplet dysfunctions have started to be recognized as causes for disease, but the underlying cell biological relationships and molecular mechanisms are still largely enigmatic [[2, 3]].

This special issue of FEBS Letters entitled “Lipid droplets in health and disease” aims at providing a broad view of our current understanding of lipid droplet functions in physiological and pathological states. Sixteen review articles highlight recent key discoveries around the lipid droplet life cycle, important technological advances in the field, and insights into the cell biology underlying inherited and acquired diseases related to altered lipid storage.

Lipid droplets are formed at the endoplasmic reticulum (ER), where neutral lipids are synthesized by membrane resident enzymes. These neutral lipids are initially soluble within the ER phospholipid bilayer, but eventually phase-separate at higher concentrations into lipid lenses, which grow by addition of further neutral lipid molecules and ultimately bud to the cytosol [[4-6]]. Beside the neutral lipid synthesizing enzymes, further proteins are required in the lipid droplet biogenesis process that enable control over the lipidome, proteome, morphology, and finally metabolic dynamics of the emerging organelle. A key player in lipid droplet formation is the conserved seipin protein. Pedro Carvalho and colleagues describe recent mechanistic insights into the molecular roles of seipin and its partner proteins [[7]]. Julia Mahamid and colleagues provide a broad overview of the numerous key contributions of electron microscopy techniques to our understanding of lipid droplet form and function, ranging from initial insights into its unique phospholipid monolayer-based architecture to recent structures of key players in lipid droplet biology such as the seipin complex [[8]]. Jennifer Sapia and Stefano Vanni discuss in a Perspective article recent advancements and challenges in employing molecular dynamics simulations to contribute to our understanding of the molecular basis of lipid droplet biogenesis and protein targeting to the lipid droplet surface [[9]].

Once formed, lipid droplets can further grow either by acquiring lipids from the ER, or by fusing with other lipid droplets in a

Tumor cells can express the immune checkpoint protein programmed death-1 (PD-1), but how cancer cell-intrinsic PD-1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell-intrinsic PD-1. Dox upregulates PD-1 mRNA while reducing PD-1 protein levels in tumor cells. Although Dox shortens the PD-1 half-life, it fails to directly induce PD-1 degradation. Instead, we observe that Dox promotes the interaction between peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1) and PD-1, facilitating NGLY1-mediated PD-1 deglycosylation and destabilization. The maintenance of PD-1 sensitizes tumor cells to Dox-mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD-1 in response to Dox and highlights a potential role of cancer cell-intrinsic PD-1 in Dox-mediated antitumor effects.

The identification of chemicals that modulate plant development and adaptive responses to stresses has attracted increasing attention for agricultural applications. Recent basic studies have identified functional amino acids that are essential for plant organogenesis, indicating that amino acids can regulate plant growth. In this study, we newly identified 2-aminopimelic acid (2APA), a nonproteinogenic amino acid, as a novel bioactive compound involved in root morphogenesis. This biological effect was confirmed in several plant species. Our phenotypic analysis revealed that the bioactive 2APA is an l-form stereoisomer. Overall, our study identified a promising root growth regulator and provided insight into the intricate metabolism related to root morphology.

Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques and molecular and cell biology research have revealed that CS are more complex than what originally thought, and as they are extremely dynamic, they can remodel their shape, composition, and functions in accordance with metabolic and environmental changes and can occur between more than two organelles. Here, we describe how recent studies led to the identification of a three-way mitochondria–ER–lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis, and balance. We also summarize the properties and functions of key protein components localized at the mitochondria–ER–lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter-organelle communication and cooperation within cells.