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Exposure to fine particulate matter (PM2.5) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5‐induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5‐accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE−/− mice liver suggested that PM2.5 activated the miR‐200a‐3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR‐200a‐3p and glucose metabolism disorder. Knockout of miR‐200a‐3p in L02 cells revealed that miR‐200a‐3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5‐induced liver metabolic dysregulation by regulating ER stress via miR‐200a‐3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution‐related liver metabolism disorders. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, the endoplasmic reticulum (ER) is constructed as a network of tubules and sheets that exist in one continuous membrane system. Several classes of integral membrane protein have been shown to shape ER membranes. Functional studies using mutant proteins have begun to reveal the significance of ER morphology and membrane dynamics. In this review, we discuss the common protein modules and mechanisms that generate the characteristic shape of the ER. We also describe the cellular functions closely related to ER morphology, particularly contacts with other membrane systems, and their potential roles in the development of multicellular organisms. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) membrane forms an elaborate network of tubules and sheets that is continuously remodeled. This dynamic behavior requires membrane fusion that is mediated by dynamin-like GTPases: the atlastins in metazoans and Sey1p and related proteins in yeast and plants. Crystal structures of the cytosolic domains of these membrane proteins and biochemical experiments can now be integrated into a model that explains many aspects of the molecular mechanism by which these membrane-bound GTPases mediate membrane fusion. [ABSTRACT FROM AUTHOR]

How is the characteristic shape of an organelle generated? Recent work has provided insight into how the tubular network of the endoplasmic reticulum (ER) is formed. The tubules themselves are shaped by the reticulons and DP1/Yop1p, whereas their fusion into a network is brought about by membrane-bound GTPases that include the atlastins, Sey1p, and RHD3. [Copyright &y& Elsevier]

Summary: The endoplasmic reticulum (ER) consists of tubules that are shaped by the reticulons and DP1/Yop1p, but how the tubules form an interconnected network is unknown. Here, we show that mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins. The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro. Depletion of the atlastins or overexpression of dominant-negative forms inhibits tubule interconnections. The Sey1p GTPase in S. cerevisiae is likely a functional ortholog of the atlastins; it shares the same signature motifs and membrane topology and interacts genetically and physically with the tubule-shaping proteins. Cells simultaneously lacking Sey1p and a tubule-shaping protein have ER morphology defects. These results indicate that formation of the tubular ER network depends on conserved dynamin-like GTPases. Since atlastin-1 mutations cause a common form of hereditary spastic paraplegia, we suggest ER-shaping defects as a neuropathogenic mechanism. [ABSTRACT FROM AUTHOR]

Abstract: The endoplasmic reticulum (ER) is involved in many critical processes, including protein and lipid synthesis and calcium storage. Morphologically, the ER can be divided into two subdomains: a network of interconnected tubules and interspersed sheets. Until recently, how these different compartments form in a continuous membrane system was unclear. Several classes of integral membrane proteins have been identified in the ER; the reticulons and DP1/Yop1p play roles in the generation of ER tubules, and possibly in stabilizing ER sheets, atlastins and Sey1p are dynamin-like GTPases that facilitate tubular network formation by mediating ER membrane fusion, and Climp63, p180, and kinectin are enriched in ER sheets and influence their formation. In this review, we summarize recent advances in our understanding of how these proteins participate in ER shaping. We also discuss possible mechanisms for regulating ER morphology via the cytoskeleton. Lessons learned about sculpting the ER membrane may be applicable to other organelles. [Copyright &y& Elsevier]

Regulated phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) by the endoplasmic reticulum (ER) stress-activated protein kinase PERK modulates protein synthesis and couples the production of ER client proteins with the organelle's capacity to fold and process them. PERK activation by ER stress is known to involve transautophosphorylation, which decorates its unusually long kinase insert loop with multiple phosphoserine and phosphothreonine residues. We report that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex. This switch correlates with a marked change to the protease sensitivity pattern, which is indicative of a major conformational change in the PERK kinase domain upon activation. Although it is dispensable for catalytic activity, PERK's kinase insert loop is required for substrata binding and for eIF2α phosphorylation in viva. Our findings suggest a novel mechanism for eIF2 recruitment by activated PERK and for unidirectional substrate flow in the phosphorylation reaction. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is the main harbor for newly synthesized proteins in eukaryotic cells. Through a continuous membrane network of sheets and tubules, the ER hosts secretory proteins, integral membrane proteins, and luminal proteins of the endomembrane system. These proteins are translated by ribosomes outside the ER and require subsequent integration into or translocation across the lipid bilayer of the ER. They are then modified post-translationally and folded in the ER. Some of these proteins are packaged into coat protein complex II–coated vesicles for export. Here, we review recent advances in understanding the mechanism of protein translocation and transmembrane domain insertion in the ER, summarize new insights into selective cargo packaging, and discuss the roles of ER morphological dynamics in these processes. [ABSTRACT FROM AUTHOR]

Reticulon and REEP family of proteins stabilize the high curvature of endoplasmic reticulum (ER) tubules. Plasmodium berghei Yop1 (PbYop1) is a REEP5 homolog in Plasmodium. Here, we characterize its function using a gene‐knockout (Pbyop1∆). Pbyop1∆ asexual stage parasites display abnormal ER architecture and an enlarged digestive vacuole. The erythrocytic cycle of Pbyop1∆ parasites is severely attenuated and the incidence of experimental cerebral malaria is significantly decreased in Pbyop1∆‐infected mice. Pbyop1∆ sporozoites have reduced speed, are slower to invade host cells but give rise to equal numbers of infected HepG2 cells, as WT sporozoites. We propose that PbYOP1's disruption may lead to defects in trafficking and secretion of a subset of proteins required for parasite development and invasion of erythrocytes. Furthermore, the maintenance of ER morphology in different parasite stages is likely to depend on different proteins. [ABSTRACT FROM AUTHOR]

Summary In eukaryotic cells, organelles and the cytoskeleton undergo highly dynamic yet organized interactions capable of orchestrating complex cellular functions. Visualizing these interactions requires noninvasive, long-duration imaging of the intracellular environment at high spatiotemporal resolution and low background. To achieve these normally opposing goals, we developed grazing incidence structured illumination microscopy (GI-SIM) that is capable of imaging dynamic events near the basal cell cortex at 97-nm resolution and 266 frames/s over thousands of time points. We employed multi-color GI-SIM to characterize the fast dynamic interactions of diverse organelles and the cytoskeleton, shedding new light on the complex behaviors of these structures. Precise measurements of microtubule growth or shrinkage events helped distinguish among models of microtubule dynamic instability. Analysis of endoplasmic reticulum (ER) interactions with other organelles or microtubules uncovered new ER remodeling mechanisms, such as hitchhiking of the ER on motile organelles. Finally, ER-mitochondria contact sites were found to promote both mitochondrial fission and fusion. Graphical Abstract Highlights • Super-resolution live-cell imaging up to 266 fps at 97-nm resolution • Hitchhiking interactions among organelles remodel ER and mitochondrial networks • ER-mitochondrion contacts promote coalescence of mitochondrial membranes • Collision of late endosomes or lysosomes carried along microtubules split ER tubules A new approach for visualizing dynamic processes within cells offers insight into membrane-membrane contact interactions and microtubule function. [ABSTRACT FROM AUTHOR]