Intracellular Lipid Homeostasis and Trafficking in Autophagy

Goyal, Shreya; Robinson, Meaghan R.; Segarra, Verónica A.; Richard, J.

doi:10.5772/intechopen.89683

Cited by 4 publications

(4 citation statements)

References 52 publications

(157 reference statements)

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“…This furthers the idea that trafficking defects are intricately linked to other neurotoxic defects as it is not inherently clear if trafficking restoration is a direct effect of the small molecule or a secondary effect resulting from the small molecule alleviating other markers of toxicity. Further, the identified targets of the NAB scaffold ( 2a , b ) and 1,2,4-oxadiazole scaffold ( 3a , b ) are not directly implicated in trafficking regulation itself but are instead associated with the ubiquitination system − (Rsp5/Nedd4) and fatty acid metabolism − (Ole1/SCD), pathways that respectively are dependent upon or directly affect endomembrane trafficking. The identification of targets by subsequent chemical genetic screening demonstrates the utility of phenotypic screens for discovery of active small molecules as enzymes Nedd4 and SCD may not have inherently be the focus of a targeted drug discovery platform for alleviation of neurotoxicity.…”

Section: Phenotypic Screening Identifies Structurally Diverse Small M...mentioning

confidence: 99%

Small Molecule Improvement of Trafficking Defects in Models of Neurodegeneration

Hatstat

Pupi

Reinhart

et al. 2021

ACS Chem. Neurosci.

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Disrupted cellular trafficking and transport processes are hallmarks of many neurodegenerative disorders (NDs). Recently, efforts have been made toward developing and implementing experimental platforms to identify small molecules that may help restore normative trafficking functions. There have been a number of successes in targeting endomembrane trafficking with the identification of compounds that restore cell viability through rescue of protein transport and trafficking. Here, we describe some of the experimental platforms implemented for small molecule screening efforts for rescue of trafficking defects in neurodegeneration. A survey of phenotypically active small molecules identified to date is provided, including a summary of medicinal chemistry efforts and insights into putative targets and mechanisms of action. In particular, emphasis is put on ligands that demonstrate activity in more than one model of neurodegeneration as retention of phenotypic activity across ND models suggests conservation of biological targets across NDs.

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Section: Phenotypic Screening Identifies Structurally Diverse Small M...mentioning

confidence: 99%

Small Molecule Improvement of Trafficking Defects in Models of Neurodegeneration

Hatstat

Pupi

Reinhart

et al. 2021

ACS Chem. Neurosci.

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“…Maintaining integrity and fluidity of cellular membranes, generating neutral lipids for storage or shuttling fatty acids (FA) into mitochondria for beta oxidation are some of the fundamental constituents of the process called lipid homeostasis [ 1 , 2 , 3 ]. In this process, the availability of free fatty acids (FFA) is a major driving force, with different tissues tolerating varying FFA levels [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte Proteome Alterations Induced by Individual and Combinations of Common Free Fatty Acids

Gindlhuber

Schinagl

Liesinger

et al. 2022

IJMS

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Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our understanding of the development of non-alcoholic fatty liver disease, we treated a human hepatoma cell line model, HepG2, with increasing concentrations of common fatty acids, namely myristic, palmitic and oleic acid. To reproduce more physiologically representative conditions, we also included combinations of these fatty acids and monitored the cellular response with an in-depth proteomics approach and imaging techniques. The two saturated fatty acids initially presented a similar phenotype of a dose-dependent decrease in growth rates and impaired lipid droplet formation. Detailed analysis revealed that the drop in the growth rates was due to delayed cell-cycle progression following myristic acid treatment, whereas palmitic acid led to cellular apoptosis. In contrast, oleic acid, as well as saturated fatty acid mixtures with oleic acid, led to a dose-dependent increase in lipid droplet volume without adverse impacts on cell growth. Comparing the effects of harmful single-fatty-acid treatments and the well-tolerated fatty acid mixes on the cellular proteome, we were able to differentiate between fatty-acid-specific cellular responses and likely common lipotoxic denominators.

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“…These key steps and the core autophagy‐related (Atg) proteins that mediate and regulate them are evolutionarily conserved across all autophagy pathways, including starvation‐induced bulk autophagy and cargo‐selective autophagy pathways. 13 , 14 , 15 , 16 While vacuoles and lysosomes can serve as storage and/or recycling depots for cells, their delimiting membranes host critical signaling events for autophagy induction such as the inactivation of target of rapamycin (TOR).…”

Section: Introductionmentioning

confidence: 99%

Vps501, a novel vacuolar SNX‐BAR protein cooperates with the SEA complex to regulate TORC1 signaling

Goyal

Segarra

Nitika

et al. 2022

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The sorting nexins (SNXs), constitute a diverse family of molecules that play varied roles in membrane trafficking, cell signaling, membrane remodeling, organelle motility and autophagy. In particular, the SNX-Bin-Amphiphysin-Rvs (BAR) proteins, a SNX subfamily characterized by a C-terminal dimeric BAR lipid curvature domain and a conserved Phox-homology domain, are of great interest. In budding yeast, many SNX-BAR proteins have well-characterized endo-vacuolar trafficking roles. Phylogenetic analyses allowed us to identify an additional SNX-BAR protein, Vps501, with a novel endovacuolar role. We report that Vps501 uniquely localizes to the vacuolar membrane and has physical and genetic interactions with the SEA complex to regulate TORC1 inactivation. We found cells displayed a severe deficiency in starvation-induced/nonselective autophagy only when SEA complex subunits are ablated in combination with Vps501, indicating a cooperative role with the SEA complex during TORC1 signaling during autophagy induction. Additionally, we found the SEACIT complex becomes destabilized in vps501Δsea1Δ cells, which resulted in aberrant endosomal TORC1 activity and subsequent Atg13 hyperphosphorylation. We have also discovered that the vacuolar localization of Vps501 is dependent upon a direct interaction with Sea1 and a unique lipid binding specificity that is also required for its function.

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Intracellular Lipid Homeostasis and Trafficking in Autophagy

Cited by 4 publications

References 52 publications

Small Molecule Improvement of Trafficking Defects in Models of Neurodegeneration

Small Molecule Improvement of Trafficking Defects in Models of Neurodegeneration

Hepatocyte Proteome Alterations Induced by Individual and Combinations of Common Free Fatty Acids

Vps501, a novel vacuolar SNX‐BAR protein cooperates with the SEA complex to regulate TORC1 signaling

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