FEBS Letters最新文献

Rising atmospheric CO₂ negatively affects plant iron (Fe) content, yet the underlying mechanisms remain poorly understood. Here, we identified More Iron under elevated CO₂ (MIC) as a new player involved in Fe homeostasis under elevated CO₂ in Arabidopsis thaliana. MIC is a previously uncharacterized transmembrane protein which we found predominantly localized to the Golgi apparatus. Loss of MIC function results in increased Fe content under elevated CO₂, effectively mitigating the Fe decline observed in plants. MIC protein abundance is reduced in roots under elevated CO₂, suggesting post-transcriptional regulation of protein stability. This work identifies MIC as a novel component in the plant response to elevated CO₂, with potential implications for improving the nutritional quality of crops under climate change.

The mechanisms supporting progression of metastatic prostate cancer (PCa) in adipocyte-rich bone marrow remain unclear. We hypothesized that stearoyl-coenzyme A desaturase (SCD) promotes PCa survival in bone by modulating stress responses and regulating lipid peroxidation. We show that SCD-high PCa cells are sensitive to SCD loss, showing smaller spheroids, reduced mTOR signaling, and elevated endoplasmic reticulum (ER) stress. SCD expression is further augmented by adipocytes, and SCD loss induces DNA damage and repair activation only with adipocyte exposure. In vivo, pharmacological SCD inhibition reduces tumor size and increases ER stress and DNA damage in SCD-high-expressing bone tumors. These findings suggest SCD plays a role in redox regulation and DNA repair sensitivity, with therapeutic potential for targeting DNA repair pathways in combination with SCD inhibition. Impact statement This study reveals that stearoyl-CoA desaturase (SCD) supports prostate cancer growth in adipocyte-rich bone by regulating redox balance and DNA repair responses, uncovering a metabolic mechanism linking lipid metabolism to genomic stability and suggesting therapeutic potential for combining SCD and DNA repair pathway inhibition.

Universal stress proteins (USPs) have remained an enigma since their first description by Nystrom and Neidhardt in 1992. Despite being upregulated under diverse stresses and found across a range of bacterial species, decades of studies suggested only general and potentially redundant protective functions for USPs. Recent studies have uncovered that USPs are critical regulators of bacterial survival processes in Actinobacteria, most notably in Mycobacterium tuberculosis, one of the most prolific and lethal of human pathogens. This brief review places these recent studies in the context of earlier publications and discusses their importance for future USP research, our understanding of these regulatory proteins, and novel therapeutic options that these proteins present in Mycobacterium tuberculosis, related Actinobacteria, and across diverse bacterial species.

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.

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.

SETDB1, a H3K9 methyltransferase involved in nuclear transcriptional silencing, also localizes to the cytoplasm through unclear mechanisms. Here, we identify cell density as key regulator of SETDB1 subcellular localization and demonstrate its role in modulating the Hippo signaling pathway. Under low-density culture, SETDB1 distributes between nucleus and cytoplasm, whereas high-density culture triggers nuclear exclusion and proteasomal degradation. SETDB1 depletion reduces YAP1 phosphorylation and increases nuclear YAP1 accumulation. Transcriptomic analysis of SETDB1 knockout cells revealed upregulation of YAP1–TEAD1 target genes (YTGs). Immunoprecipitation experiments showed that SETDB1 is recruited to YTG promoters via TEAD1 and competes with YAP1 for TEAD1 binding. These findings reveal that SETDB1 regulates Hippo pathway output through YAP1 phosphorylation modulation and competitive transcriptional repression.