scholarly journals Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting

2020 ◽  
Vol 54 (4) ◽  
pp. 471-487.e7 ◽  
Author(s):  
Maria-Jesus Olarte ◽  
Siyoung Kim ◽  
Morris E. Sharp ◽  
Jessica M.J. Swanson ◽  
Robert V. Farese ◽  
...  
Author(s):  
Maria-Jesus Olarte ◽  
Jessica M.J. Swanson ◽  
Tobias C. Walther ◽  
Robert V. Farese

JCI Insight ◽  
2021 ◽  
Author(s):  
Yoshiaki Morishita ◽  
Aaron P. Kellogg ◽  
Dennis Larkin ◽  
Wei Chen ◽  
Suryakiran Vadrevu ◽  
...  

Autophagy ◽  
2017 ◽  
Vol 13 (7) ◽  
pp. 1130-1144 ◽  
Author(s):  
Tsung-Huang Tsai ◽  
Elaine Chen ◽  
Lan Li ◽  
Pradip Saha ◽  
Hsiao-Ju Lee ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dorota Raj ◽  
Ola Billing ◽  
Agnieszka Podraza-Farhanieh ◽  
Bashar Kraish ◽  
Oskar Hemmingsson ◽  
...  

AbstractCisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.


Hepatology ◽  
2015 ◽  
Vol 62 (2) ◽  
pp. 615-626 ◽  
Author(s):  
Fiona O'Mahony ◽  
Kevin Wroblewski ◽  
Sheila M. O'Byrne ◽  
Hongfeng Jiang ◽  
Kara Clerkin ◽  
...  

2010 ◽  
Vol 22 (8) ◽  
pp. 1262 ◽  
Author(s):  
Xing Yang ◽  
Kylie R. Dunning ◽  
Linda L.-Y. Wu ◽  
Theresa E. Hickey ◽  
Robert J. Norman ◽  
...  

Lipid droplet proteins regulate the storage and utilisation of intracellular lipids. Evidence is emerging that oocyte lipid utilisation impacts embryo development, but lipid droplet proteins have not been studied in oocytes. The aim of the present study was to characterise the size and localisation of lipid droplets in mouse oocytes during the periovulatory period and to identify lipid droplet proteins as potential biomarkers of oocyte lipid content. Oocyte lipid droplets, visualised using a novel method of staining cumulus–oocyte complexes (COCs) with BODIPY 493/503, were small and diffuse in oocytes of preovulatory COCs, but larger and more centrally located after maturation in response to ovulatory human chorionic gonadotrophin (hCG) in vivo, or FSH + epidermal growth factor in vitro. Lipid droplet proteins Perilipin, Perilipin-2, cell death-inducing DNA fragmentation factor 45-like effector (CIDE)-A and CIDE-B were detected in the mouse ovary by immunohistochemistry, but only Perilipin-2 was associated with lipid droplets in the oocyte. In COCs, Perilipin-2 mRNA and protein increased in response to ovulatory hCG. IVM failed to induce Perilipin-2 mRNA, yet oocyte lipid content was increased in this context, indicating that Perilipin-2 is not necessarily reflective of relative oocyte lipid content. Thus, Perilipin-2 is a lipid droplet protein in oocytes and its induction in the COC concurrent with dynamic reorganisation of lipid droplets suggests marked changes in lipid utilisation during oocyte maturation.


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