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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

Preprint posted on April 15, 2020 https://www.biorxiv.org/content/10.1101/2020.04.06.027847v1

Cellular FITness: Lipid and Protein homeostasis go hand in hand

Selected by Madhuja Samaddar

Background:

Lipid droplets (LDs), which are ER-derived membrane-bound storages of neutral lipids in the cytoplasm, were long perceived to be inert energy reserves. Increasing evidence in recent years points to their key roles in maintaining energy homeostasis and signaling (1). Disrupted lipid metabolism and alterations in LD homeostasis, underlies a variety of metabolic diseases including obesity, atherosclerosis, fatty liver disease, and lipid storage diseases (2). Does lipid homeostasis also influence protein homeostasis? Multiple reports have indicated that this could be the case. For example, LD biogenesis is enhanced by ER stress induction (3). On the other hand, proteostasis pathways are reprogrammed under conditions of disrupted lipid metabolism, indicating that these processes likely do not operate in isolation (4). This new study from Shyu et al. investigates the role of Saccharomyces cerevisiae FIT (fat storage inducing transmembrane) proteins as a link between lipid and protein homeostasis, especially under conditions of cellular stress. Members of this conserved family of ER-resident proteins are known to regulate lipid droplet biogenesis at the ER membrane (5).

 

Key Findings:

Using a combination of genetic and biochemical analyses, the authors show that the ScFIT protein Scs3 is required for regulating LD morphology and phospholipid homeostasis in the ER. LDs of abnormal morphology are retained by the ER in the absence of functional Scs3 protein and in a double mutant also lacking Ire1. Further Scs3 is found to be essential for survival in the absence of Ire1, the exclusive Unfolded protein Response (UPR) transducer in yeast.

Using a split-ubiquitin based yeast two hybrid system for membrane protein interactors, they also probe the interactome of Scs3. Interestingly, the interacting partners include multiple members of cellular proteostasis networks, ranging from chaperones to components of the ubiquitin proteasome system. Finally, the absence of ScFIT proteins impairs the clearance of (ER-associated degradation) ERAD client proteins, and Scs3 alone is sufficient to reverse this defect. Together these findings lend further support to the interdependence of lipid and protein homeostasis at the ER and identify Scs3 as a candidate operating at the interface. However, whether aberrant lipid accumulation in the ER impairs protein clearance or ScFIT proteins directly modulate protein quality control pathways remains an open question.

Model for ScFIT proteins in regulating lipid and protein homeostasis at the ER (Reproduced with permission from the authors of the preprint; Shyu et al. 2020)

 

Why is this important?

Lipid droplets interact with multiple other cellular organelles via membrane contacts and serve as a dynamic means of intracellular communication (6). The involvement of LD biogenesis regulators in processes beyond lipid homeostasis lend support to the idea that cellular stress responses can be dynamically integrated for coordinated action.

 

Questions for the authors:

  1. Starvation-induced autophagy upregulates LD biogenesis (7). Given the identification of vacuolar function related proteins in the ScFIT interactome, do you expect the loss of Scs3 to also have an effect on autophagic induction?
  2. Do you expect that overexpression of ScFIT family proteins in cultured mammalian cells would also boost their proteostasis capacity, in addition to stimulating lipid droplet biogenesis? If we view LD synthesis as a protective response, would you then expect that targeting ScFIT proteins for upregulation can achieve a dual protective purpose?

 

References:

1. Lipid Droplets Finally Get a Little R-E-S-P-E-C-T (2009). https://doi.org/10.1016/j.cell.2009.11.005

2. Lipid Droplets in Health and Disease (2017). https://doi.org/10.1186/s12944-017-0521-7

3. Pharmacological ER stress promotes hepatic lipogenesis and lipid droplet formation (2012). https://www.ncbi.nlm.nih.gov/pubmed/22347525

4. The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network (2012). https://doi.org/10.1016/j.molcel.2012.08.016

5. Evolutionarily conserved gene family important for fat storage (2008). https://doi.org/10.1073/pnas.0708579105

6. Dynamics and functions of lipid droplets (2019). https://doi.org/10.1038/s41580-018-0085-z

7. DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function During Starvation-Induced Autophagy (2017). https://doi.org/10.1016/j.devcel.2017.06.003

 

Tags: cellular stress responses, lipid droplets, lipid homeostasis, proteostasis, yeast

Posted on: 26th April 2020 , updated on: 27th April 2020

doi: https://doi.org/10.1242/prelights.19358

Read preprint (2 votes)




  • Response from the authors

    Guillaume Thibault shared

    Hi Madhuja,

    Thank you for taking the time to highlight our preprint. You have done a fantastic job summarizing our work and you raised excellent questions.

    You asked “Starvation-induced autophagy upregulates LD biogenesis (7). Given the identification of vacuolar function related proteins in the ScFIT interactome, do you expect the loss of Scs3 to also have an effect on autophagic induction?

    Tunicamycin-induced UPR upregulates SCS3 gene expression in addition to promote LD formation. Our data including the interactome, TEM images, and protein degradation assays validate the role of Scs3 in regulating LD biogenesis as well as being necessary to maintain ERAD functionality. Consequently, Scs3 eases ER stress. Based on our findings, we speculate that the loss of SCS3 may induce autophagy, perhaps not due to impaired LD biogenesis, but as a result of defective LDs which in turn interfere with cells to cope with various stresses. Autophagy can induce LD biogenesis in budding yeast, but whether LD directly modulates autophagy remains unclear.

    We identified vacuole related proteins that interact with Scs3 in our MYTH assay. These candidates are intriguing as LDs are commonly found within the vacuole whereas Scs3 is localized at the membrane of the ER. Studies have shown that in the absence of TG lipases (particularly important during starvation as they breakdown lipids to provide energy), yeast cells survive though microlipophagy. Supposing impairs LD biogenesis by the loss of SCS3, it is conceivable that it will exacerbate the ability of cells to sequester LDs to the autophagy pathway. Therefore, cells would be unable to tap on the available lipid reserve.

    Alternatively, Scs3 protein could be essential to catalyze the last step of autophagy. Vacuolar integral membrane protein Atg22, identified in our MYTH assay, is required for the efflux of amino acids during autophagic body breakdown. Perhaps, assessing the transcriptomic and proteomic landscape of ScFIT mutant strains could reveal pathways unsuspected to be regulated by ScFIT proteins. Regardless, we can speculate from our data that Scs3 promotes the last step of the autophagy pathway. The release of the autophagolysosome content might be modulated through Scs3 to maintain homeostasis. Possibly, the lack of SCS3 may disrupt this essential step in the autophagy pathway. This avenue should be explored in future studies.

     

    You also asked “Do you expect that overexpression of ScFIT family proteins in cultured mammalian cells would also boost their proteostasis capacity, in addition to stimulating lipid droplet biogenesis? If we view LD synthesis as a protective response, would you then expect that targeting ScFIT proteins for upregulation can achieve a dual protective purpose?

    The protective response that can be achieved by the accumulation of LDs, especially when cells are exposed to stress. The rates of lipid biogenesis and lipid degradation are finely tuned allowing cells to maintain lipid homeostasis and so to adjust to stress conditions. Rather than a passive cytoplasmic structure for lipid storage, recent studies have proven that LDs are dynamic and involved in myriads of cellular signaling pathways. Our findings show that overexpressing ScFIT proteins promote proteostasis capacity of budding yeast cells. However, we should be cautious before jumping to the conclusion that similar outcomes will be replicated in mammalian cells. For instance, the ablation of FIT2 in mammalian cells dramatically reduce the number of LDs while having little effect in budding yeast. Only future studies will tell us.

    Nevertheless, the possibility that the overexpression of ScFIT in mammalian cells promotes proteostasis is exciting. It could be exploited in the context of metabolic diseases. For instance, it has been showed that patients with type 2 diabetes have lower expression of FIT2 gene in adipose tissue compared to healthy subject (Agrawal et al., FASEB J. 2019, doi. 10.1096/fj.201701321RR). Scs3 might protect cells through LD biogenesis or protein quality control pathways. Either way, Scs3 could be a promising therapeutic target to exploit.

     

    Thanks again for your interest in our work and for providing a wonderful platform to stimulate scientific discussions.

    Wei Sheng Yap and Guillaume Thibault

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