FEBS Letters最新文献

Circadian regulation in peripheral cells depends on calcium dynamics, but the upstream mechanisms remain unclear. We identify endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2) as a regulator of the peripheral clock. Knockdown and overexpression of ERLIN2 in C2C12 skeletal muscle cells show that ERLIN2 positively regulates cryptochrome circadian regulator 1/2 (CRY1/2) transcription and maintains rhythmicity. ERLIN2 regulates inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ release and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)-mitogen-activated protein kinase (MAPK)-cAMP response element-binding protein (CREB) pathway. ATP induced IP₃R-dependent Ca²⁺ transients, CREB phosphorylation, and Per1 expression, reshaping circadian rhythm, effects blocked by IP₃R, Ca²⁺, or CaMKII inhibition. CRY1 enhances and CRY2 suppresses CREB signaling, establishing a feedback loop with ERLIN2. This ERLIN2-Ca²⁺-CREB-CRY1/2 axis couples membrane contact sites to circadian regulation. Impact statement This study reveals ERLIN2 as a key regulator linking calcium signaling to circadian rhythms, establishing an ERLIN2-Ca²⁺-CREB-CRY1/2 axis that advances understanding of cellular clock control.

Recently, we showed that the Per-ARNT-Sim (PAS) domain-containing phosphoglycerate kinase from Leishmania major (LmPAS-PGK) is imported into both the glycosome and the lysosome; however, the mechanism underlying its dual targeting has remained unclear. LmPAS-PGK contains a C-terminal tripeptide sequence and two dileucine base motifs. To investigate the roles of these sorting signals, we generated different complement cell lines from null mutants by transfecting constructs encoding the wild-type protein, an L230A/L231A mutant, the C-terminal tripeptide deleted variant (∆^525-527), a dileucine motif deleted variant (∆^504-508), and a double-deletion mutant (∆^525-527/∆^504-508). Our results demonstrate that the dileucine motif governs the lysosomal targeting of LmPAS-PGK, whereas the C-terminal tripeptide is required for glycosomal localization. Deletion of both motifs abolished trafficking to either organelle, leading to cytosolic redistribution. Notably, ∆^525-527, ∆^504-508, and ∆^525-527/∆^504-508 cells displayed lower virulence compared with control cells in infected macrophages, underscoring the importance of proper LmPAS-PGK localization in Leishmania pathogenicity. Impact statement Here, we show the dileucine motif of PAS-PGK of Leishmania major governs its lysosomal targeting, whereas its C-terminal tripeptide is required for glycosomal localization. Cells lacking these domains displayed lower virulence compared with control cells in infected macrophages. These results increase our understanding of intracellular trafficking, as well as host-parasite interactions.

Cystathionine γ-synthase (CGS) and cystathionine γ-lyase (CGL) have highly similar amino acid sequences. CGS catalyzes the generation of cystathionine from acylated l-homoserine and l-cysteine, whereas CGL catalyzes the decomposition of cystathionine to produce l-cysteine. Lactobacillus plantarum is a unique bacterium containing two open reading frames of CGL/CGS enzymes in its genome. Structural studies of LpCGS and LpCGL may provide insights into their reaction specificities. In the present study, we elucidated the structure and enzymatic function of LpCGS. We found that LpCGS has substrate specificity toward acetylated rather than succinylated l-homoserine. LpCGS has the characteristic residues E55 and V232 in the substrate-binding pocket, which synergistically confer substrate specificity toward acetylated l-homoserine. These results may facilitate the development of inhibitors of l-methionine and l-cysteine biosynthetic pathways.

Biological systems are fundamentally rhythmic, with oscillations emerging at multiple scales, from intracellular gene circuits to organ-level coordination. Many of these rhythms, including the circadian clock, arise from feedback-driven genetic networks that interact to produce coherent temporal organisation. In this review, we examine the circadian system as a model for understanding the dynamics of coupled biological oscillators. We introduce the core theoretical concepts of delayed feedback, nonlinearity and coupling, and show how these principles govern the emergence of synchronisation, entrainment, and complex dynamics across cellular populations and tissues. Drawing on tools from nonlinear dynamics, we explore how oscillator models help explain robustness, plasticity, and failure modes in circadian systems. Finally, we discuss how this theoretical framework informs experimental design and translational applications in circadian medicine, from optimising drug timing to understanding rhythm disruptions in disease.

The THO complex was initially identified in Saccharomyces cerevisiae with five subunits: Hpr1p, Tho2p, Mft1p, Thp2p, and Tex1p. It plays a major role in mRNA processing and nuclear export. Here, we aimed to identify the putative homologs in Schizosaccharomyces pombe. Among eight candidates, genetic analysis showed tho1, tho2, and pci2 are essential, while mutants of tho5 and tho7 exhibited growth defects along with genome instability and impaired mRNA export. Subcellular localization studies showed all putative homologs except Tho3 are localized to the nucleus, whereas Pci2 localizes to the nuclear envelope. Yeast two-hybrid and immunoprecipitation-mass spectrometry confirmed Tho1, Tho2, Tho5, and Tho7 form the core THO complex. This work defines the THOC complex in S. pombe and supports Pci2 as a component of TREX-2 at the nuclear periphery during mRNA export.

Understanding molecular interactions at the host-pathogen interface is essential to decipher infection mechanisms and develop new therapies. Bacterial surface proteins and host-derived bacterial binding proteins (HBBPs) govern colonization, adhesion, and immune modulation, but are difficult to study due to low abundance and transient interactions. Advances in chemical biology and proteomics now enable high-resolution mapping of these dynamic surfaces. Techniques such as bioorthogonal labeling, photo-crosslinking, click chemistry, and enzymatic proximity labeling expand our ability to identify surface-exposed and transient complexes. Combined with mass spectrometry and bioinformatics, they offer an integrated view of host-microbe crosstalk, revealing novel virulence factors and antigenic targets. This review highlights innovative labeling strategies advancing infection biology and immune recognition.

The inositol phosphate signaling pathway has emerged as a compelling therapeutic target in a broad range of diseases, including osteoporosis, viral infections, metabolic disorders, and cancer metastasis. Inositol phosphates regulate essential cellular processes such as insulin signaling, nucleotide synthesis, DNA damage response, and phosphate homeostasis. Given this wide spectrum of physiological roles, the kinases responsible for inositol phosphate biosynthesis-namely IP3Ks, IPMK, ITPK1, IP5-2 K, IP6Ks, and PPIP5Ks-have attracted increased interest over the past decade. Accumulating evidence supports their potential as drug targets in the treatment of obesity, cancer, and aging-related conditions. In this review, structure-guided strategies, particularly those informed by high-resolution crystal structures, are examined for their role in accelerating the discovery and development of small-molecule inhibitors targeting inositol phosphate kinases. Structural insights, advances in therapeutic development, and future directions for improving inhibitor specificity and efficacy are discussed.

COL4A1/A2 disorders are rare, congenital, multisystem disorders caused by mutations in the COL4Α1 or COL4Α2 genes, which encode α chains of collagen IV. There are no curative treatments at present, and intervention is focused on managing the symptoms. Associazione Famiglie COL4A1/A2 was established in 2021 to provide support for patients and their families, and to promote research into the basic mechanisms of the disorders. As part of FEBS Letters's series on patient advocacy for rare disorders, we interviewed Francesca Manodoro, Vice-President and Treasurer of Associazione Famiglie COL4A1-A2, Tom Van Agtmael, Professor of Matrix Biology and Disease at the University of Glasgow, and Simona Balestrini, Associate Professor of Child Neurology at the University of Florence, on the history of the organisation, ongoing research into these conditions, and the challenges in securing funding for research and translating basic research findings into the clinic.

Circadian clocks are endogenous timekeeping mechanisms that are phylogenetically widespread. Despite the immense diversity of bacterial life, to date, clocks have been identified in few bacterial species. The cyanobacterial clock is understood in great detail, and the roles of its clock proteins in other types of timing mechanisms and in stress resistance are being studied in an ever-growing range of species. Studies of host-associated microbiomes have shown that host and microbial rhythmicity impact one another reciprocally. However, bacterial rhythms have primarily been studied in species in isolation or in host-associated microbiomes. Here, we summarize the state of the field of microbial chronobiology and propose the hypothesis that rhythmicity could be an emergent property of microbial interactions in free-living bacterial communities.

Collaboration has become an essential pillar of modern biological research. From international genome initiatives to interdisciplinary multi-omics projects, research in the life sciences increasingly relies on (multi)institutional teamwork. Yet, many collaborations fail to deliver on their promises of innovation, efficiency, and scientific impact. Morten T. Hansen's concept of 'disciplined collaboration' (2009) offers a valuable framework for understanding why collaboration sometimes hinders rather than helps research productivity. In this article, Hansen's principles are repurposed to the context of biological research in universities and research institutes. It is substantiated that selective, well-managed, and strategically aligned collaborations, rather than indiscriminate cooperations, lead to sustainable scientific advancement. The discussion of this paper explores the four major barriers to effective collaboration in academia, the three organizational levers proposed by Hansen, and the evaluative processes necessary for implementing disciplined collaboration in research environments. Finally, Hansen's views on institutional strategies are adapted to cultivate collaborative excellence within life science research in academic institutions.