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Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis

Peter Shyu, Wei Sheng Yap, Maria L. Gaspar, Stephen A. Jesch, Charlie Marvalim, William A. Prinz, Susan A. Henry, View ORCID ProfileGuillaume Thibault
doi: https://doi.org/10.1101/2020.04.06.027847
Peter Shyu
1 Nanyang Technological University;
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  • For correspondence: pshyu001@e.ntu.edu.sg
Wei Sheng Yap
1 Nanyang Technological University;
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  • For correspondence: weisheng.yap@ntu.edu.sg
Maria L. Gaspar
2 Cornell University;
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  • For correspondence: mlg32@cornell.edu
Stephen A. Jesch
2 Cornell University;
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  • For correspondence: saj23@cornell.edu
Charlie Marvalim
1 Nanyang Technological University;
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  • For correspondence: cmarvali001@e.ntu.edu.sg
William A. Prinz
3 NIDDK/NIH
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  • For correspondence: wprinz@helix.nih.gov
Susan A. Henry
2 Cornell University;
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  • For correspondence: sah42@cornell.edu
Guillaume Thibault
1 Nanyang Technological University;
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  • ORCID record for Guillaume Thibault
  • For correspondence: thibault@ntu.edu.sg
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Abstract

Lipid droplets (LDs) have long been regarded as inert cytoplasmic organelles with the primary function of housing excess intracellular lipids. More recently, LDs have been strongly implicated in conditions of lipid and protein dysregulation. The fat storage inducing transmembrane (FIT) family of proteins comprises of evolutionarily conserved endoplasmic reticulum (ER)-resident proteins that have been reported to induce LD formation. Here, we establish a model system to study the role of S. cerevisiae FIT homologues (ScFIT), SCS3 and YFT2, in proteostasis and stress response pathways. While LD biogenesis and basal ER stress-induced unfolded protein response (UPR) remain unaltered in ScFIT mutants, SCS3 was found to be essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1. Devoid of a functional UPR, scs3 mutants exhibited accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting a UPR-dependent compensatory mechanism for LD maturation. Additionally, SCS3 was necessary to maintain phospholipid homeostasis. Strikingly, the absence of the ScFIT proteins results in the downregulation of the closely-related Heat Shock Response (HSR) pathway. In line with this observation, global protein ubiquitination and the turnover of both ER and cytoplasmic misfolded proteins is impaired in ScFIT cells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Taken together, these suggest that ScFIT proteins may modulate proteostasis and stress response pathways with lipid metabolism at the interface between the two cellular processes.

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Posted April 15, 2020.
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Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis
Peter Shyu, Wei Sheng Yap, Maria L. Gaspar, Stephen A. Jesch, Charlie Marvalim, William A. Prinz, Susan A. Henry, Guillaume Thibault
bioRxiv 2020.04.06.027847; doi: https://doi.org/10.1101/2020.04.06.027847
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Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis
Peter Shyu, Wei Sheng Yap, Maria L. Gaspar, Stephen A. Jesch, Charlie Marvalim, William A. Prinz, Susan A. Henry, Guillaume Thibault
bioRxiv 2020.04.06.027847; doi: https://doi.org/10.1101/2020.04.06.027847

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