N6-Methyladenosine (m6A), a pivotal RNA modification, plays a critical role in carcinogenesis across multiple cancer types. YT521-B homology domain family protein 1 (YTHDF1), a binding protein of m6A, facilitates the translation of downstream targets via m6A recognition. However, the involvement of YTHDF1 in pancreatic cancer progression and its mechanistic underpinnings remain poorly understood. In this study, we observed significant upregulation of YTHDF1 in pancreatic cancer cell lines (SW1990 and PANC-1) compared to the normal human pancreatic cell line hTERT-HPNE. Functional assays revealed that YTHDF1 knockdown markedly suppressed cell proliferation and invasion, whereas its overexpression enhanced these malignant phenotypes in both SW1990 and PANC-1 cells. Mechanistically, YTHDF1 interacted with coding sequence (CDS) region of splicing factor 3B subunit 2 (SF3B2), whereas YTHDF1 downregulation reduced SF3B2 protein levels without altering its mRNA expression, suggesting post-transcriptional regulation via m6A modification. Importantly, SF3B2 overexpression rescued the suppressed proliferation and invasion caused by YTHDF1 knockdown in SW1990 and PANC-1 cells. Collectively, our findings demonstrate that YTHDF1 drives pancreatic cancer progression by enhancing SF3B2 translation through m6A modification, thereby providing novel mechanistic insights and a potential therapeutic target for pancreatic cancer.

Nuclear pore complexes (NPCs) act as gateways across the nuclear envelope for molecular transport between the nucleus and the cytoplasm in eukaryotes. NPCs consist of several subcomplexes formed by multiple copies of approximately 30 different proteins known as nucleoporins (Nups). In the fission yeast Schizosaccharomyces pombe, the NPC structure is unique, particularly in its outer ring subcomplexes, where the cytoplasmic and nucleoplasmic outer rings are composed of distinct sets of proteins. However, it remains unclear how this unique outer ring structure in S. pombe is supported by interactions between subcomplexes or individual Nups. In this study, we investigated protein-protein interactions between S. pombe Nups using mass spectrometry and identified Nups that interact with each subcomplex or a specific Nup. The cytoplasmic outer ring Nups bind to both the cytoplasmic filament Nups and the inner ring Nups, while the nucleoplasmic outer ring Nups bind to the nuclear basket Nups in addition to the inner ring Nups. Among the inner ring Nups, Nup155 interacts with most of the cytoplasmic and nucleoplasmic outer ring Nups, suggesting that Nup155 may serve as a hub supporting the uniquely asymmetric outer ring structure of the S. pombe NPC.

Post-translational modifications play crucial roles in regulating protein function. Protein methylation, occurring at lysine, arginine, and histidine, has gained attention, particularly for histone methylation. However, the mechanism and significance of protein methylation at histidine remains poorly understood. Kasai et al. developed a novel method to identify histidine-methylated proteins and discovered that γ-enolase in the mouse brain undergoes Nτ-methylation at His190. This modification reduces dimerization and enzymatic activity, suggesting this reaction plays a physiological role. This work will accelerate research on histidine methylation and help elucidate unknown phenomena in the brain.

Glycosylphosphatidylinositol (GPI) anchoring is a conserved post-translational modification in eukaryotes. This modification allows acceptor proteins to be expressed at the cell surface as GPI-anchored proteins (GPI-APs), which play critical roles in various biological processes. It has been proposed that remodelling of GPI after transferring acceptor proteins, including the PGAP1-dependent deacylation of GPI-inositol, functions as a checkpoint for transporting mature GPI-APs from the endoplasmic reticulum (ER) to the Golgi. A previous study identified several factors involved in regulating PGAP1-dependent GPI-inositol deacylation, including proteins associated with the calnexin cycles, SELT and CLPTM1. A recent report by Cao etal., revealed that the loss of TMEM41B, an ER-resident lipid scramblase, rescues the defect in GPI-inositol deacylation in SELT-KO cells. Further investigation demonstrated that TMEM41B is essential for the efficient transport of both GPI-APs and transmembrane proteins from the ER to the Golgi. The study also found that PGAP1 proteins accumulate in the ER of TMEM41B-KO cells, suggesting that perturbations in the ER-membrane lipid integrity stabilize PGAP1 proteins, thereby enhancing the PGAP1 activity within the ER. These findings highlight that defects in TMEM41B impact two distinct processes: (i) the transport of GPI-APs from the ER to the Golgi, and (ii) the deacylation of GPI-APs.

A recent study reported that isomerization of aspartyl residues (Asp) occurs in various tissues and proteins in vivo. For a comprehensive analysis of post-translational modifications, the mass spectrometry (MS)-based proteomic approach is a straightforward method; however, the isomerization of Asp does not alter its molecular weight. Therefore, a unique method is required to analyse Asp isomers using MS. Herein, we present a novel strategy, isoAsp-Quest, which is a database search-oriented isoAsp identification method. isoAsp is specifically converted to 18O-labelled Lα-Asp by the enzymatic reaction of protein L-isoaspartyl-O-methyltransferase (PIMT) in 18O water with a mass shift of 2Da, which, in principle, enables us to distinguish Asp isomers. However, in practise, a labelled Lα-Asp signal overlaps with that of endogenous Lα-Asp, making detection challenging. Therefore, degradation of the endogenous Lα-Asp peptide by AspN and subsequent removal of AspN were performed prior to the PIMT reaction. This strategy was applied to bovine lens α-crystallin. Consequently, several Asp isomerization sites, consistent with human αA-crystallin, were identified in bovine αA-crystallin, indicating that this strategy is also effective for biological proteins. Therefore, isoAsp-Quest enables the analysis of Lβ-Asp in a straightforward and rapid workflow, which may be useful for the quality control of protein products and biomarker discovery.

Recent advances in DNA sequencing technology have enabled the precise decoding of genomes in non-model organisms, providing a basis for unraveling the patterns and mechanisms of sex chromosome evolution. Studies of different species have yielded conflicting results regarding the traditional theory that sex chromosomes evolve from autosomes via the accumulation of deleterious mutations and degeneration of the Y (or W) chromosome. The concept of the ‘sex chromosome cycle,’ emerging from this context, posits that at any stage of the cycle (i.e., differentiation, degeneration, or loss), sex chromosome turnover can occur while maintaining stable sex determination. Thus, understanding the mechanisms that drive both the persistence and turnover of sex chromosomes at each stage of the cycle is crucial. In this review, we integrate recent findings on the mechanisms underlying maintenance and turnover, with a special focus on several organisms having unique sex chromosomes. Our review suggests that the diversity of sex chromosomes in the maintenance of stable sex determination is underappreciated and emphasizes the need for more research on the sex chromosome cycle.

Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.

In most organs, resources such as nutrients, oxygen and physiologically active substances are unevenly supplied within the tissue spaces. Consequently, different tissue functions are exhibited in each space. This spatial heterogeneity of tissue environments arises depending on the spatial arrangement of nutrient vessels and functional vessels, leading to continuous changes in the metabolic states and functions of various cell types from regions proximal to these vessels to distant regions. This phenomenon is referred to as 'zonation'. Traditional analytical methods have made it difficult to investigate this zonation in detail. However, recent advancements in intravital imaging, spatial transcriptomics and single-cell transcriptomics technologies have facilitated the discovery of 'zones' in various organs and elucidated their physiological roles. Here, we outline the spatial differences in the immune system within each zone of organs. This information provides a deeper understanding of organs' immune systems.