Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis
Posted on: 26 April 2020 , updated on: 27 April 2020
Preprint posted on 15 April 2020
Article now published in Journal of Cell Science at http://dx.doi.org/10.1242/jcs.248526
Categories: biochemistry, cell biology, genetics
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:
- 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?
- 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
doi: https://doi.org/10.1242/prelights.19358
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