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Nature Dec 2018The NLRP3 inflammasome, which has been linked to human inflammatory diseases, is activated by diverse stimuli. How these stimuli activate NLRP3 is unknown. Here we show...
The NLRP3 inflammasome, which has been linked to human inflammatory diseases, is activated by diverse stimuli. How these stimuli activate NLRP3 is unknown. Here we show that different NLRP3 stimuli lead to disassembly of the trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. The dTGN then serves as a scaffold for NLRP3 aggregation into multiple puncta, leading to polymerization of the adaptor protein ASC, thereby activating the downstream signalling cascade. Disruption of the interaction between NLRP3 and PtdIns4P on the dTGN blocked NLRP3 aggregation and downstream signalling. These results indicate that recruitment of NLRP3 to dTGN is an early and common cellular event that leads to NLRP3 aggregation and activation in response to diverse stimuli.
Topics: Amino Acid Sequence; Animals; HEK293 Cells; Humans; Inflammasomes; Ion Transport; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidylinositol Phosphates; Potassium; Protein Binding; Signal Transduction; trans-Golgi Network
PubMed: 30487600
DOI: 10.1038/s41586-018-0761-3 -
Immunity Dec 2022The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile inflammatory conditions. NLRP3 activity is governed by two...
The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile inflammatory conditions. NLRP3 activity is governed by two independent signals: the first signal primes NLRP3, rendering it responsive to the second signal, which then triggers inflammasome formation. Our understanding of how NLRP3 priming contributes to inflammasome activation remains limited. Here, we show that IKKβ, a kinase activated during priming, induces recruitment of NLRP3 to phosphatidylinositol-4-phosphate (PI4P), a phospholipid enriched on the trans-Golgi network. NEK7, a mitotic spindle kinase that had previously been thought to be indispensable for NLRP3 activation, was redundant for inflammasome formation when IKKβ recruited NLRP3 to PI4P. Studying iPSC-derived human macrophages revealed that the IKKβ-mediated NEK7-independent pathway constitutes the predominant NLRP3 priming mechanism in human myeloid cells. Our results suggest that PI4P binding represents a primed state into which NLRP3 is brought by IKKβ activity.
Topics: Humans; I-kappa B Kinase; Inflammasomes; Mice, Inbred C57BL; NIMA-Related Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Serine-Threonine Kinases; trans-Golgi Network; Mice; Animals
PubMed: 36384135
DOI: 10.1016/j.immuni.2022.10.021 -
Journal of Plant Research May 2022Membrane traffic is a fundamental cellular system to exchange proteins and membrane lipids among single membrane-bound organelles or between an organelle and the plasma... (Review)
Review
Membrane traffic is a fundamental cellular system to exchange proteins and membrane lipids among single membrane-bound organelles or between an organelle and the plasma membrane in order to keep integrity of the endomembrane system. RAB GTPases and SNARE proteins, the key regulators of membrane traffic, are conserved broadly among eukaryotic species. However, genome-wide analyses showed that organization of RABs and SNAREs that regulate the post-Golgi transport pathways is greatly diversified in plants compared to other model eukaryotes. Furthermore, some organelles acquired unique properties in plant lineages. Like in other eukaryotic systems, the trans-Golgi network of plants coordinates secretion and vacuolar transport; however, uniquely in plants, it also acts as a platform for endocytic transport and recycling. In this review, we focus on RAB GTPases and SNAREs that function at the TGN, and summarize how these regulators perform to control different transport pathways at the plant TGN. We also highlight the current knowledge of RABs and SNAREs' role in regulation of plant development and plant responses to environmental stimuli.
Topics: Genome-Wide Association Study; Golgi Apparatus; Plants; Protein Transport; SNARE Proteins; rab GTP-Binding Proteins; trans-Golgi Network
PubMed: 35488138
DOI: 10.1007/s10265-022-01392-x -
ELife Nov 2023A receptor protein called TGN46 has an important role in sorting secretory proteins into vesicles going to different destinations inside cells.
A receptor protein called TGN46 has an important role in sorting secretory proteins into vesicles going to different destinations inside cells.
Topics: trans-Golgi Network; Proteins; Protein Transport; Golgi Apparatus; Secretory Vesicles
PubMed: 37997893
DOI: 10.7554/eLife.93490 -
FEBS Letters Sep 2019The sorting and distribution to different final destinations of roughly a third of the membrane and secreted proteins occurs at the level of the trans-Golgi network... (Review)
Review
The sorting and distribution to different final destinations of roughly a third of the membrane and secreted proteins occurs at the level of the trans-Golgi network (TGN). This TGN mission involves efficient mechanisms of cargo recognition and activation of specific signalling pathways. This is important because protein localization is strictly connected with function, and many aberrant phenotypes may occur when a protein is missorted to the wrong cellular compartment. In this review, we briefly summarize the principal players known to be involved in TGN functions, highlighting the importance of regulatory signalling pathways and also the pathological outcomes of aberrant sorting and export events from the TGN compartment.
Topics: Animals; Humans; Protein Transport; Signal Transduction; trans-Golgi Network
PubMed: 31396955
DOI: 10.1002/1873-3468.13572 -
Proceedings of the National Academy of... Nov 2018The -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....
The -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 mutant loss of TGN () 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.
Topics: Arabidopsis; Arabidopsis Proteins; Golgi Apparatus; Golgi Matrix Proteins; Guanine Nucleotide Exchange Factors; Intracellular Signaling Peptides and Proteins; Pollen Tube; Protein Transport; trans-Golgi Network
PubMed: 30413616
DOI: 10.1073/pnas.1809206115 -
Current Opinion in Cell Biology Aug 2008The retromer is a heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of transmembrane cargo from endosomes... (Review)
Review
The retromer is a heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network. The mammalian retromer complex comprises a sorting nexin dimer composed of a still undefined combination of SNX1, SNX2, SNX5 and SNX6, and a cargo-recognition trimer composed of Vps26, Vps29 and Vps35. The SNX subunits contain PX and BAR domains that allow binding to PI(3)P enriched, highly curved membranes of endosomal vesicles and tubules, while Vps26, Vps29 and Vps35 have arrestin, phosphoesterase and alpha-solenoid folds, respectively. Recent studies have implicated retromer in a broad range of physiological, developmental and pathological processes, underscoring the critical nature of retrograde transport mediated by this complex.
Topics: Carrier Proteins; Endosomes; Humans; Protein Transport; Sorting Nexins; Vesicular Transport Proteins; trans-Golgi Network
PubMed: 18472259
DOI: 10.1016/j.ceb.2008.03.009 -
FEBS Letters Nov 2019Membrane contact sites (MCSs) between different organelles have been identified and extensively studied over the last decade. Several classes of MCSs have now... (Review)
Review
Membrane contact sites (MCSs) between different organelles have been identified and extensively studied over the last decade. Several classes of MCSs have now well-established roles, although the contacts between the endoplasmic reticulum (ER) and the trans-side of the Golgi network (TGN) have long remained elusive. Until recently, the study of ER-TGN contact sites has represented a major challenge in the field, as a result of the lack of suitable visualization and isolation techniques. Only in the last 5 years has the combination of advanced technologies and innovative approaches permitted the identification of new molecular players and the functions of ER-TGN MCSs that couple lipid metabolism and anterograde transport. Although much has yet to be discovered, it is now established that ER-TGN MCSs control phosphatidyl-4-phosphate homeostasis by coupling the cis and the trans activity of the ER-resident 4-phosphatase Sac1. In this review, we focus on recent advances on the composition and function of ER-TGN MCSs.
Topics: Biological Transport; Cell Membrane; Endoplasmic Reticulum; Lipid Metabolism; trans-Golgi Network
PubMed: 31610025
DOI: 10.1002/1873-3468.13639 -
International Journal of Molecular... Sep 2018Endocytic trafficking plays a major role in transport of incoming human papillomavirus (HPVs) from plasma membrane to the trans Golgi network (TGN) and ultimately into... (Review)
Review
Endocytic trafficking plays a major role in transport of incoming human papillomavirus (HPVs) from plasma membrane to the trans Golgi network (TGN) and ultimately into the nucleus. During this infectious entry, several cellular sorting factors are recruited by the viral capsid protein L2, which plays a critical role in ensuring successful transport of the L2/viral DNA complex to the nucleus. Later in the infection cycle, two viral oncoproteins, E5 and E6, have also been shown to modulate different aspects of endocytic transport pathways. In this review, we highlight how HPV makes use of and perturbs normal endocytic transport pathways, firstly to achieve infectious virus entry, secondly to produce productive infection and the completion of the viral life cycle and, finally, on rare occasions, to bring about the development of malignancy.
Topics: Capsid Proteins; Cell Membrane; Cell Nucleus; Endocytosis; Humans; Oncogene Proteins, Viral; Papillomaviridae; Virus Internalization; trans-Golgi Network
PubMed: 30181457
DOI: 10.3390/ijms19092619 -
Current Opinion in Cell Biology Aug 2021The sorting of secreted cargo proteins and their export from the trans-Golgi network (TGN) remains an enigma in the field of membrane trafficking; although the sorting... (Review)
Review
The sorting of secreted cargo proteins and their export from the trans-Golgi network (TGN) remains an enigma in the field of membrane trafficking; although the sorting mechanisms of many transmembrane proteins have been well described. The sorting of secreted proteins at the TGN is crucial for the release of signaling factors, as well as extracellular matrix proteins. These proteins are required for cell-cell communication and integrity of an organism. Missecretion of these factors can cause diseases such as neurological disorders, autoimmune disease, or cancer. The major open question is how soluble proteins that are not associated with the membrane are packed into TGN derived transport carriers to facilitate their transport to the plasma membrane. Recent investigations have identified novel types of protein and lipid machinery that facilitate the packing of these molecules into a TGN derived vesicle. In addition, novel research has uncovered an exciting link between cargo sorting and export in which TGN structure and dynamics, as well as TGN/endoplasmic reticulum contact sites, play a significant role. Here, we have reviewed the progress made in our understanding of these processes.
Topics: Cell Membrane; Endoplasmic Reticulum; Membrane Proteins; Protein Transport; trans-Golgi Network
PubMed: 33706234
DOI: 10.1016/j.ceb.2021.02.005