Plant cell walls are essential for growth. The cell wall hemicellulose xyloglucan (XyG) is produced in the Golgi apparatus before secretion. Loss of the Arabidopsis galactosyltransferase MURUS3 (MUR3) decreases XyG d-galactose side chains and causes intracellular aggregations and dwarfism. It is unknown how changing XyG synthesis can broadly impact organelle organization and growth. We show that intracellular aggregations are not unique to mur3 and are found in multiple mutant lines with reduced XyG D-galactose side chains. mur3 aggregations disrupt subcellular trafficking and induce formation of intracellular cell-wall-like fragments. Addition of d-galacturonic acid onto XyG can restore growth and prevent mur3 aggregations. These results indicate that the presence, but not the composition, of XyG side chains is essential, likely by ensuring XyG solubility. Our results suggest that XyG polysaccharides are synthesized in a highly substituted form for efficient secretion and then later modified by cell-wall-localized enzymes to fine-tune cell wall properties.

Alzheimer\'s disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double-knock-out (PS1/2-/-) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2-/- fibroblasts. Active GSK-3β was increased in PS1/2-/- fibroblasts, and inhibiting GSK3β activity in PS1/2-/- fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2-/- fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.

Patients with central neuronal damage may suffer severe consequences, but effective therapies remain unclear. Previous research has established the transplantation of neural stem cells that generate new neurons to replace damaged ones. In a new field of scientific research, the extracellular secretion of NPSCs (NSPCs-ES) has been identified as an alternative to current chemical drugs. Many preclinical studies have shown that NSPCs-ES are effective in models of various central nervous system diseases (CNS) injuries, from maintaining functional structures at the cellular level to providing anti-inflammatory functions at the molecular level, as well as improving memory and motor functions, reducing apoptosis in neurons, and mediating multiple signaling pathways. The NSPC-ES can travel to the damaged tissue and exert a broad range of therapeutic effects by supporting and nourishing damaged neurons. However, gene editing and cell engineering techniques have recently improved therapeutic efficacy by modifying NSPCs-ES. Consequently, future research and application of NSPCs-ES may provide a novel strategy for the treatment of CNS diseases in the future. In this review, we summarize the current progress on these aspects.

Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson\'s disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca2+ levels.

VAMP721 and VAMP722, play crucial roles in membrane fusion at post-Golgi compartments. They are involved in cell plate formation, recycling, endocytosis, and secretion. While individual SNARE actors and regulators exhibit significant overlap, specificity is achieved through distinct combinations of these components. Cytokinesis-related SNAREs traffic as preformed CIS-complexes, which require disassembly by the NSF/αSNAP chaperoning complex to facilitate subsequent homotypic fusion at the cell plate. Recent findings suggest a similar mechanism may operate during secretion. Regulation of VAMP721 activity involves interactions with tethers, GTPases, and Sec1/Munc18 proteins, along with a newly discovered phosphorylation at Tyrosine residue 57. These advances provide valuable insights into the fascinating world of cellular trafficking and membrane fusion.

The protein translocon at the endoplasmic reticulum comprises the Sec61 translocation channel and numerous accessory factors that collectively facilitate the biogenesis of secretory and membrane proteins. Here, we leveraged recent advances in cryo-electron microscopy (cryo-EM) and structure prediction to derive insights into several novel configurations of the ribosome-translocon complex. We show how a transmembrane domain (TMD) in a looped configuration passes through the Sec61 lateral gate during membrane insertion; how a nascent chain can bind and constrain the conformation of ribosomal protein uL22; and how the translocon-associated protein (TRAP) complex can adjust its position during different stages of protein biogenesis. Most unexpectedly, we find that a large proportion of translocon complexes contains RAMP4 intercalated into Sec61\'s lateral gate, widening Sec61\'s central pore and contributing to its hydrophilic interior. These structures lead to mechanistic hypotheses for translocon function and highlight a remarkably plastic machinery whose conformations and composition adjust dynamically to its diverse range of substrates.

Platelet apoptosis is irreversible under current storage conditions in blood banks. Studies have shown that programmed cell death ligand 1 (PD-L1) in tumour cells is required for neoplastic progression, tumour recurrence and metastasis by regulating apoptosis. However, whether PD-L1 is involved in storage-induced apoptosis in platelets remains poorly understood. In this study, we explored whether PD-L1 on platelets participated in the regulation of storage-induced apoptosis under blood bank conditions, as well as the underlying mechanism. Several apoptotic events in platelets from humans and PD-L1-knockout mice during storage under blood bank conditions were measured. The mechanism by which storage-induced apoptosis was regulated by platelet-intrinsic PD-L1 signalling was further investigated. Our results showed that PD-L1 in platelets progressively decreased. There was a strong negative correlation between platelet PD-L1 expression and the phosphatidylserine (PS) externalization rate and cleaved caspase-3 level and a positive correlation with anti-apoptosis protein Bcl-xl. Ex vivo, PD-L1-/- platelets stored at 22 °C showed rapid apoptosis via an intrinsic mitochondria-dependent pathway over time. Likewise, inhibiting PD-L1 signalling with BMS-1166 accelerated apoptosis by intrinsic mitochondria-dependent pathway. Coimmunoprecipitation analysis revealed that PD-L1 could bind AKT in platelets, and the binding capacity of both showed a progressive decrease with time. Finally, the decrease in PD-L1 expression levels during storage could be attributed to a complex process of progressive secretion. Therefore, platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway, which is expected to become a target for alleviating platelet storage lesions (PSLs) under current blood bank conditions.

Histopathological heterogeneity in the human pancreas is well documented; however, functional evidence at the tissue level is scarce. Herein, we investigate in situ glucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in donors without diabetes (ND; n = 15), positive for one islet autoantibody (1AAb+; n = 7), and with type 1 diabetes (T1D; <14 months duration, n = 5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features are comparable across regions in ND. In T1D, insulin secretion and beta-cell volume are significantly reduced within all regions, while glucagon and enzymes are unaltered. Beta-cell volume is lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ are consistent across the PH, PB, and PT. This study supports low inter-regional variation in pancreas slice function and, potentially, increased metabolic demand in 1AAb+.

Siderophores are a class of small molecules renowned for their high iron binding capacity, essential for all life forms requiring iron. This article provides a detailed review of the diverse classifications, and biosynthetic pathways of siderophores, with a particular emphasis on siderophores synthesized via nonribosomal peptide synthetase (NRPS) and non-NRPS pathways. We further explore the secretion mechanisms of siderophores in microbes and plants, and their role in regulating bioavailable iron levels. Beyond biological functions, the applications of siderophores in medicine, agriculture, and environmental sciences are extensively discussed. These applications include biological pest control, disease treatment, ecological pollution remediation, and heavy metal ion removal. Through a comprehensive analysis of the chemical properties and biological activities of siderophores, this paper demonstrates their wide prospects in scientific research and practical applications, while also highlighting current research gaps and potential future directions.

Introduction: The CH1 domain of IgG antibodies controls assembly and secretion, mediated by the molecular chaperone BiP via the endoplasmic reticulum protein quality control (ERQC) mechanism. However, it is not clear whether the variable domains are necessary for this process. Methods: Here, we generated IgG1 antibodies in which the V domain (VH and/or VL) was either removed or replaced, and then assessed expression, assembly, and secretion in HEK293 cells. Results: All Ig variants formed a covalent linkage between the Cγ1 and Cκ, were successfully secreted in an assembled form. Replacement of the cognate Vκ with a non-secretory pseudo Vκ (ψVκ) hindered secretion of individual or assembled secretion of neither heavy chains (HCs) nor light chains (LCs). The ψLC (ψVκ-Cκ) exhibited a less folded structure compared to the wild type (wt) LC, as evidenced by enhanced stable binding to the molecular chaperone BiP and susceptibility to proteolytic degradation. Molecular dynamics simulation demonstrated dramatic alterations in overall structure of ψFab (Fd-ψLC) from wt Fab. Discussion: These findings suggest that V domains do not initiate HC:LC assembly and secretion; instead, the critical factor governing IgG assembly and secretion is the CH-CL pairing. Additionally, the structural integrity of the VL domain is crucial for IgG secretion. These data offer valuable insight into the design of bioactive molecules based on an IgG backbone.