Explore the vast range of titles available.

The trans-Golgi network (TGN) is an essential tubular-vesicular organelle derived from the Golgi and functions as an independent sorting and trafficking hub within the cell. However, the molecular regulation of TGN biogenesis remains enigmatic. Here we identified an Arabidopsis mutant loss of TGN (lot) that is defective in TGN formation and sterile due to impaired pollen tube growth in the style. The mutation leads to overstacking of the Golgi cisternae and significant reduction in the number of TGNs and vesicles surrounding the Golgi in pollen, which is corroborated by the dispersed cytosolic distribution of TGN-localized proteins. Consistently, deposition of extracellular pectin and plasma membrane localization of kinases and phosphoinositide species are also impaired. Subcellular localization analysis suggests that LOT is localized on the periphery of the Golgi cisternae, but the mutation does not affect the localization of Golgi-resident proteins. Furthermore, the yeast complementation result suggests that LOT could functionally act as a component of the guanine nucleotide exchange factor (GEF) complex of small Rab GTPase Ypt6. Taken together, these findings suggest that LOT is a critical player for TGN biogenesis in the plant lineage.

The Golgi complex is a highly dynamic and tightly regulated cellular organelle with essential roles in the processing as well as the sorting of proteins and lipids. Its structure undergoes rapid disassembly and reassembly during normal physiological processes, including cell division, migration, polarization, differentiation, and cell death. Golgi dispersal or fragmentation also occurs in pathological conditions, such as neurodegenerative diseases, infectious diseases, congenital disorders of glycosylation diseases, and cancer. In this review, current knowledge about both structural organization and morphological alterations in the Golgi in physiological and pathological conditions is summarized together with the methodologies that help to reveal its structure.

Varicella-zoster virus (VZV) infection downregulates surface major histocompatibility complex class I (MHC-I) expression and retains MHC-I in the Golgi complex of infected cells. However, the underlying mechanism is not fully understood. The VZV IE4 protein is a multifunctional protein that is essential for VZV infection. In this study, the human leucocyte antigen C (HLA-C) protein was identified as a novel cellular factor associated with IE4. Ectopically expressed IE4 co-localizes with HLA-C, sequesters HLA-C to the Golgi complex and downregulates cellular surface MHC-I. VZV, with a mutated Golgi localization signal in IE4, denoted as mutated IE4 (mIE4) VZV, was constructed. In mIE4 VZV-infected cells, the cellular surface MHC-I was restored, and HLA-C was not retained in the Golgi complex. In summary, for the first time, we demonstrate a novel role of VZV IE4 in interfering with the MHC-I presentation pathway, suggesting that it may contribute to the evasion of host antiviral adaptive immunity.

Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side of the Golgi apparatus, the TOR-autophagy spatial coupling compartment (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid— and Rag guanosine triphosphatase—dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells' catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.

Understanding the genetic causes of diseases that affect pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a congenital disorder with two known etiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the potentially novel disease gene TMEM167A. All had neonatal diabetes (diagnosed at <6 months) and severe microcephaly, and 5 also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient's variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.

The Golgi apparatus is known to underpin many important cellular homeostatic functions, including trafficking, sorting and modifications of proteins or lipids. These functions are dysregulated in neurodegenerative diseases, cancer, infectious diseases and cardiovascular diseases, and the number of disease-related genes associated with Golgi apparatus is on the increase. Recently, many studies have suggested that the mutations in the genes encoding Golgi resident proteins can trigger the occurrence of diseases. By summarizing the pathogenesis of these genetic diseases, it was found that most of these diseases have defects in membrane trafficking. Such defects typically result in mislocalization of proteins, impaired glycosylation of proteins, and the accumulation of undegraded proteins. In the present review, we aim to understand the patterns of mutations in the genes encoding Golgi resident proteins and decipher the interplay between Golgi resident proteins and membrane trafficking pathway in cells. Furthermore, the detection of Golgi resident protein in human serum samples has the potential to be used as a diagnostic tool for diseases, and its central role in membrane trafficking pathways provides possible targets for disease therapy. Thus, we also introduced the clinical value of Golgi apparatus in the present review.

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome. COPA regulates Golgi to ER transport, and mutations lead to autoinflammation and disease through poorly understood mechanisms. Here, the authors show that disease-causing COPA variants prevent STING transport from the Golgi to the ER, leading to cGAS-independent activation of the STING pathway.

Key Points The trans -Golgi network (TGN) is an assembly of pleiomorphic tubular membranes that emanates from the trans -Golgi pole. It has multiple crucial roles in intracellular transport as a sorting node for secretory cargo, a biosynthetic centre for sphingolipids and the interface between the exocytic and endocytic pathways. The TGN is an extremely dynamic structure, and its extent (size and number of tubules) largely depends on the amount of cargo and membrane flowing through it. We therefore propose that this organelle is an assembly of cargo-sorting domains under extrusion as tubules for export out of the Golgi complex. The main destinations of TGN-derived carriers are the apical and basolateral plasma membrane, the early and late endosomes, the secretory granules and other specialized compartments in specialized cells. Each of these destinations corresponds to at least one carrier type, although different carriers might ferry specific cargo proteins to the same acceptor organelle. The final destination of each specific cargo type is determined by the sorting signals in the cargo molecule. These signals are decoded by a complex cytosolic machinery, within which coat proteins and adaptors have a major role. The formation of these pleiomorphic tubular TGN carriers can be divided into three main stages: cargo sorting into a forming tubule; extrusion of the tubular carrier along microtubules by molecular motors; and fission of the elongated tubule into a free carrier. Each of these stages involves a multi-component machinery, only parts of which have been identified to date. Future research in the TGN area will require the unravelling of the further components and their assigning to the appropriate carrier formation stage within specific Golgi export pathways. Another key challenge will be to determine the regulatory mechanisms by which the functions of the TGN are controlled and coordinated both at the organelle level within the secretory pathway, and between the TGN and other global cellular functions and responses. The trans -Golgi network (TGN) is a major sorting centre for lipids and proteins that lies at the crossroads of endocytic and exocytic pathways. Recent studies have started to elucidate the molecular machineries that function in sorting and trafficking at the TGN. The composition and identity of cell organelles are dictated by the flux of lipids and proteins that they receive and lose through cytosolic exchange and membrane trafficking. The trans -Golgi network (TGN) is a major sorting centre for cell lipids and proteins at the crossroads of the endocytic and exocytic pathways; it has a complex dynamic structure composed of a network of tubular membranes that generate pleiomorphic carriers targeted to different destinations. Live-cell imaging combined with three-dimensional tomography has recently provided the temporal and topographical framework that allows the assembly of the numerous molecular machineries so far implicated in sorting and trafficking at the TGN.

We acquired molecular-resolution structures of the Golgi within its native cellular environment. VitreousChlamydomonascells were thinned by cryo-focused ion beam milling and then visualized by cryo-electron tomography. These tomograms revealed structures within the Golgi cisternae that have not been seen before. Narrow trans-Golgi lumina were spanned by asymmetric membrane-associated protein arrays that had ∼6-nm lateral periodicity. Subtomogram averaging showed that the arrays may determine the narrow central spacing of the trans-Golgi cisternae through zipper-like interactions, thereby forcing cargo to the trans-Golgi periphery. Additionally, we observed dense granular aggregates within cisternae and intracisternal filament bundles associated with trans-Golgi buds. These native in situ structures provide new molecular insights into Golgi architecture and function.