“…1e ). All screen images and analyses are deposited at the Lipid Droplet Knowledge Portal 33 ( http://lipiddroplet.org/ ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Original screen images and quantification results are available at the Lipid Droplet Knowledge Portal 33 ( http://lipiddroplet.org/ ). Please select ‘Fly gene’ under ‘Query a gene’ and search by gene name.…”
Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD–ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.
“…1e ). All screen images and analyses are deposited at the Lipid Droplet Knowledge Portal 33 ( http://lipiddroplet.org/ ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Original screen images and quantification results are available at the Lipid Droplet Knowledge Portal 33 ( http://lipiddroplet.org/ ). Please select ‘Fly gene’ under ‘Query a gene’ and search by gene name.…”
Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD–ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.
“…Genomic analyses also identified the CIDEB gene, which is involved in LD metabolism, as being enriched for somatic mutations linked to fatty liver disease relative to healthy control ( 47 ), while deletion of LAMP2A in mouse liver caused hepatic steatosis due to defective lipophagy ( 48 ). Thus, given the importance of LD biology in the etiology of liver disease, more needs to be understood about the mechanisms controlling LD accumulation and turnover ( 49 , 50 ).…”
Hepatic steatosis is a major etiological factor in hepatocellular carcinoma (HCC), but factors causing lipid accumulation leading to HCC are not understood. We identify BNIP3 (a mitochondrial cargo receptor) as an HCC suppressor that mitigates against lipid accumulation to attenuate tumor cell growth. Targeted deletion of
Bnip3
decreased tumor latency and increased tumor burden in a mouse model of HCC. This was associated with increased lipid in
bnip3
−/−
HCC at early stages of disease, while lipid did not accumulate until later in tumorigenesis in wild-type mice, as
Bnip3
expression was attenuated. Low BNIP3 expression in human HCC similarly correlated with increased lipid content and worse prognosis than HCC expressing high BNIP3. BNIP3 suppressed HCC cell growth by promoting lipid droplet turnover at the lysosome in a manner dependent on BNIP3 binding LC3. We have termed this process “mitolipophagy” because it involves the coordinated autophagic degradation of lipid droplets with mitochondria.
“…Lipid droplets store triacylglycerol and sterol esters, and a number of enzymes exploit the unique properties of lipid droplets and their monolayer membrane to both sense and regulate the amount and composition of lipids stored within [ 70 ]. A recent burst of research has revealed that lipid droplets are functionally and spatially heterogeneous, and excitingly, modulating specific subpopulations of lipid droplets prolongs organismal lifespan [ 71–73 ]. Specifically, some lipid droplets are spatially segregated to the cell periphery, where they form contacts with plasma membrane and are linked with lipid trafficking mechanisms distinct from those found in perinuclear lipid droplets.…”
Advances in public health have nearly doubled life expectancy over the last century, but this demographic shift has also changed the landscape of human illness. Today, chronic and age-dependent diseases dominate the leading causes of morbidity and mortality worldwide. Targeting the underlying molecular, genetic and cell biological drivers of the aging process itself appears to be an increasingly viable strategy for developing therapeutics against these diseases of aging. Towards this end, one of the most exciting developments in cell biology over the last decade is the explosion of research into organelle contact sites and related mechanisms of inter-organelle communication. Identification of the molecular mediators of inter-organelle tethering and signaling is now allowing the field to investigate the consequences of aberrant organelle interactions, which frequently seem to correlate with age-onset pathophysiology. This review introduces the major cellular roles for inter-organelle interactions, including the regulation of organelle morphology, the transfer of ions, lipids and other metabolites, and the formation of hubs for nutrient and stress signaling. We explore how these interactions are disrupted in aging and present findings that modulation of inter-organelle communication is a promising avenue for promoting longevity. Through this review, we propose that the maintenance of inter-organelle interactions is a pillar of healthy aging. Learning how to target the cellular mechanisms for sensing and controlling inter-organelle communication is a key next hurdle for geroscience.
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