FEBS Letters最新文献

EXPRESSION OF CONCERN: M. Demasi and Kelvin J.A Davies, “ Proteasome Inhibitors Induce Intracellular Protein Aggregation and Cell Death by an Oxygen-Dependent Mechanism,” FEBS Letters 542, no. 1-3 (2003): 89-94, 10.1016/S0014-5793(03)00353-3.

This Expression of Concern is for the above article, published online on 12 April 2003 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Michael Brunner; the Federation of European Biochemical Societies; and John Wiley & Sons Ltd. The Expression of Concern has been agreed upon due to the identification of overlaps between the 21% Oxygen and 3% Oxygen control panels in Figure 4, and between the 3% Oxygen, 5 μM lactacystin, and 3% Oxygen, 5 μM NLVS panels in Figure 4. Due to the length of time that has passed since publication, the authors were unable to provide their original data. The journal has decided to issue this Expression of Concern to inform and alert readers to the above issue.

The ability to align circadian phase to specific cues, or 'entrainment', is a defining feature of a circadian rhythm. Entrainment is critical for useful circadian function, as it enables organisms to determine the specific time of day to perform temporally restricted behavioural and physiological activities, ranging from sleep to cell division. While mammals have long been known to entrain their circadian rhythm, recent work has shed light on how this is achieved in every single cell, all of which maintain their own individual circadian oscillation. Here I will highlight the current understanding of how the major entraining cues of light, feeding and temperature are communicated to cells to alter their phase. Knowledge of the mechanisms of cellular entrainment has the capacity to impact both fundamental understanding of circadian rhythms and our application of cellular circadian research to real-world problems, including shift work.

Vibrio cholerae, the causative agent of cholera, uses surface proteins such as the repeats-in-toxin (RTX) adhesin FrhA to colonize hosts and initiate infection. Blocking bacterial adhesion represents a promising therapeutic strategy to treat infections without promoting drug resistance. FrhA contains a peptide-binding domain (PBD) that is key for hemagglutination, human epithelial cell binding, and V. cholerae biofilm formation. Previous studies identified a lead pentapeptide ligand with the sequence Ala-Gly-Tyr-Thr-Asp (AGYTD) that blocks V. cholerae colonization of the mouse small intestine at high micromolar concentrations. In this study, a structure-guided approach identified a minimal D-amino acid-containing tripeptide motif with higher affinity for the FrhA-PBD and predicted metabolic stability. Our results contribute to the development of anti-adhesion strategies to combat infections. Impact statement Our study elucidates the molecular basis of peptide recognition by the Vibrio cholerae adhesin FrhA and develops minimal D-amino-acid peptides that block adhesion with nanomolar affinity. These findings advance understanding of RTX adhesins and provide a structural blueprint for next-generation anti-adhesion therapeutics against cholera and related infections.

It has been proposed that the regulatory Sit4-associated protein subunit 3 (SAPS3) of protein phosphatase 6 (PP6C) acts as an AMP-activated protein kinase (AMPK) inhibitor by recruiting PP6C to dephosphorylate AMPKα-T172. While we confirm this interaction in HEK293 cells, we find limited evidence for a SAPS3–AMPK interaction in metabolically perturbed liver and skeletal muscle from humans and mice. Across fasting, high-fat diet feeding and exercise conditions, co-immunoprecipitation assays failed to detect endogenous SAPS3–AMPK and PP6C–AMPK interactions. These findings challenge the physiological relevance of SAPS3/PP6C as regulators of AMPK in mature tissues and highlight the need for further investigation into the regulation of AMPK by protein phosphatases in vivo.

Circadian clocks allow for the physiological anticipation of daily environmental changes. A circadian rhythm in intracellular Mg²⁺ was recently discovered in multiple eukaryotes. Given the pivotal role for Mg²⁺ in metabolism, Mg²⁺ rhythms could affect cellular energy expenditure over the daily cycle. To probe the potential mechanisms underlying the generation of cellular Mg²⁺ rhythms, we present a phylogenetic analysis of Mg²⁺ transport proteins. Extensive conservation was observed for ancestral prokaryotic proteins, identifying these as candidate proteins mediating Mg²⁺ rhythms across eukaryotes. We also posit that shared allosteric regulation of Mg²⁺ transport proteins might underlie Mg²⁺ rhythms and propose a reciprocal feedback model between the rhythmic usage of Mg²⁺ and rhythmic transport activity.

Vesicle fusion events are crucial for the survival of Giardia lamblia as they drive nutrient uptake and morphological stage transitions. Unlike most eukaryotes, Giardia has a minimal vesicular trafficking machinery. We report a rare exception to this minimalism wherein two paralogues of N-ethylmaleimide-sensitive factor (NSF) are present in this parasite. Localization studies indicate that these highly homologous paralogues-GlNSF₁₁₂₆₈₁ and GlNSF₁₁₄₇₇₆-likely function independently under various stress conditions, as GlNSF₁₁₂₆₈₁ remains at peripheral vesicles, while the major pool of GlNSF₁₁₄₇₇₆ redistributes to anterior flagella-associated structures. These paralogues also exhibit selective affinity for the α-soluble NSF attachment proteins (Glα-SNAPs). This selectivity stems from sequence divergences near their N termini. The two GlNSFs colocalize and coimmunoprecipitate, indicating the presence of a heterohexameric 20S complex in trophozoites. This study is the first to report the presence of a heterohexameric 20S complex and reveals adaptive specialization of vesicle trafficking machinery within a reduced eukaryotic system. Impact statement Here we report that a unicellular parasitic protist, Giardia lamblia, has two NSF paralogues, which is a rarity in eukaryotes. Although they share a high degree of homology, they are likely to discharge independent functions, especially under stress conditions.

Mammalian cells express seven distinct phosphoinositide species: PI(3)P, PI(4)P, PI(5)P, PI(3,4)P₂, PI(3,5)P₂, PI(4,5)P₂, and PI(3,4,5)P₃. With the rapid development of labeling, imaging, and manipulation tools, our understanding of the spatial distribution, functions, and regulation of these phosphoinositides has advanced significantly. Tightly regulated by lipid kinases, phosphatases, and lipid transfer proteins, each phosphoinositide exhibits a unique yet dynamic spatial distribution at both subcellular and suborganelle levels. This distinct spatial organization is critical for controlling membrane trafficking, defining organelle identity and function, mediating signal transduction, and supporting other essential cellular processes. Dysregulation of spatial phosphoinositide signaling has been linked to various human diseases. In this review, we provide a brief overview of current insights into the spatial organization of phosphoinositide signaling, highlighting its key roles in regulating membrane dynamics and signal transduction at the plasma membrane, endosomes and lysosomes, the Golgi apparatus, the ER, and the nucleus.

Dipeptidyl peptidase IV (DPPIV) family proteases are classically defined by their strict removal of N-terminal dipeptides from substrates bearing a proline or alanine at the P₁ position. Here, we report that both Caenorhabditis elegans DPF-3 and human DPP4 (hDPP4) possess previously unrecognized tripeptidyl peptidase activity in addition to dipeptidyl peptidase activity. This activity plays a key role in the processing of the WAGO-1 protein N-terminus, which is essential for proper small-RNA loading, germline genome defense, and fertility. Kinetic analyses using the fluorogenic substrate H-Met-Gly-Pro-AMC further demonstrated that, in vitro, DPF-3 and hDPP4 can liberate AMC. These findings potentially expand the substrate repertoire of DPPIV proteases, suggesting that these proteases could function as versatile N-terminal processors, with important implications for nascent protein maturation.

The HtrA family of proteins is known for its dual role as chaperones and proteases. In Helicobacter pylori (H. pylori), HtrA's chaperone and proteolytic activities are crucial for the bacterium's survival and successful host infection. Compared to other HtrA homologs in Gram-negative bacteria, HtrA of H. pylori (HtrA_Hp) is rather well-understood. HtrA is localized in two cellular compartments, performing critical functions within the bacterial periplasm as well as in the extracellular milieu. This review aimed to summarize the current knowledge on HtrA_Hp and provide comprehensive information about (i) the structure, oligomerization, and general properties of HtrA_Hp, (ii) its chaperone and proteolytic activity in the stress response and the protein quality control system in the periplasm, and (iii) the functional role of HtrA_Hp in opening lateral cell junction complexes of epithelial cells as an important step in infectivity. Due to its essential physiological role and its contribution to the pathologic consequences of infection, HtrA represents a highly attractive target for novel therapeutic strategies.

Wound healing in the skin is a coordinated process in which the extracellular matrix (ECM) plays a central regulatory role. While the structural constituents of the ECM, such as collagens and elastin, are responsible for the shape and mechanical strength of the tissue, the modulatory functions of the ECM are largely mediated by nonstructural matricellular proteins. These proteins bind to structural ECM components, cell surface receptors and other extracellular molecules to fine-tune cellular behaviour throughout the different phases of wound healing. The signalling cascades evoked by matricellular proteins modulate key cellular processes, including proliferation, migration and differentiation-functions essential for effective tissue regeneration. This review provides an update about the mechanisms by which matricellular proteins orchestrate the wound healing process.