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Molecularly distinct cores coexist inside stress granules

Luca Cirillo, Adeline Cieren, Monica Gotta

Preprint posted on June 07, 2019 https://www.biorxiv.org/content/10.1101/663955v1

Getting to the core of cellular stress – superresolution microscopy reveals that core proteins G3BP1 and UBAP2L localise to distinct spots within stress granules

Selected by Tessa Sinnige

Categories: cell biology

Background

Cells have evolved a variety of ways to cope with stress. Under conditions such as heat shock or oxidative stress, global translation is halted so that the cell can prioritise its resources to processes essential for its survival. Stalled mRNAs accumulate together with RNA-binding proteins and other interaction partners in cytoplasmic foci termed stress granules. The formation of these granules has been suggested to be mediated by liquid-liquid phase separation of the mRNA and associated proteins, but the granules have also been shown to contain stable cores (1). Whereas the protein G3BP1 has long been known to be essential for the assembly of stress granules, recent proteomics studies have in addition implied UBAP2L as a regulator of stress granule formation (2, 3). This finding inspired the authors of this preprint to further examine the role of UBAP2L, aiming to shed more light on the process of stress granule assembly.

 

The authors find that UBAP2L…

  • … is required for the assembly of stress granules upon various types of stress. Whereas arsenite treatment is most commonly used as a robust inducer of stress granule formation, stress granule assembly and composition may vary depending on the particular stress conditions. Consistent with a recent report (4), the authors find that a range of conditions including ER stress, proteasome inhibition, heat shock and mitochondrial stress all lead to recruitment of UBAP2L to cytoplasmic granules, whereas depletion of UBAP2L prevents the formation of stress granules.
  • … has the properties of a stress granule core protein. Using 3D-STED microscopy, the authors observe that similar to G3BP1, UBAP2L is localised to discrete foci within stress granules. Based on Fluorescence Recovery After Photobleaching (FRAP) experiments on live cells with endogenously tagged UBAP2L, the authors conclude that the protein is partially present in a relatively immobile fraction, which is also consistent with the properties of a core protein.
  • … localises to stress granule cores that are distinct from those containing G3BP1. Whereas the two proteins form particles of similar size within the stress granules, the 3D-STED microscopy data show that they do not co-localise. This finding is confirmed by expansion microscopy on fixed and stained HeLa cells.
Fig 1G from the preprint showing the distinct localisation of UBAP2L and G3BP1 within a stress granule. Reproduced under a CC-BY-NC-ND 4.0 International license.

 

  • … acts upstream of G3BP1 in stress granule formation. Upon depletion or knock-down of G3BP1 and its close homologue G3BP2, UBAP2L still localises to cytosolic granules after arsenite treatment. However, the granules are fewer in number and smaller in size, confirming that G3BP1 and 2 do play a role in the maturation of stress granules.
  • … acts downstream of the inhibition of translation. Depleting UBAP2L does not affect the phosphorylation of eIF2α or the disassembly of polysomes, which are the earliest steps in the response to arsenite-induced stress which halt translation. Instead, the localisation of both UBAP2L and G3BP1 to stress granules depends on the presence of the 48S preinitiation complex that is released upon polysome disassembly.

 

Why I chose this preprint

I find stress granules fascinating for two reasons: 1) their potential role in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which the stress-granule associated protein TDP-43 forms cytoplasmic aggregates; and 2) they are a prime example of the membrane-less organelles that are thought to arise from liquid-liquid phase separation. However, the architecture of stress granules is more intricate than just a phase-separated soup, and super-resolution microscopy had already revealed the existence of solid cores surrounded by a liquid shell (1). This preprint adds yet another puzzling layer of complexity, suggesting that distinct cores of different protein compositions exist. The organisation of stress granules under healthy and diseased conditions may hold many more surprises in store!

 

Questions

Is this only the tip of the iceberg? Do the authors expect there will be just these two different types of stress granule cores, or could there be innumerable variations in stress granule core composition?

UBAP2L was previously identified in proteomics studies using G3BP1 as a bait (2, 3). Would this interaction be mediated by the mobile fraction of the two proteins? Would there be a way to determine the specific protein composition of the UBAP2L- and the G3BP1-containing cores?

 

References

  1. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A and Parker R (2016) ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 164: 487–498
  2. Markmiller S, Soltanieh S, Server KL, Mak R, Jin W, Fang MY, Luo E-C, Krach F, Yang D, Sen A, Fulzele A, Wozniak JM, Gonzalez DJ, Kankel MW, Gao F-B, Bennett EJ, Lécuyer E and Yeo GW (2018) Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules. Cell 172: 590-604.e13
  3. Youn JY, Dunham WH, Hong SJ, Knight JDR, Bashkurov M, Chen GI, Bagci H, Rathod B, MacLeod G, Eng SWM, Angers S, Morris Q, Fabian M, Côté JF and Gingras AC (2018) High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Mol. Cell 69: 517-532.e11
  4. Huang C, Chen Y, Dai H, Zhang H, Xie M, Zhang H, Chen F, Kang X, Bai X and Chen Z (2019) UBAP2L arginine methylation by PRMT1 modulates stress granule assembly. Cell Death Differ. 2019: 10.1038/s41418-019-0350-5

Tags: expansion microscopy, stress granules, superresolution microscopy

Posted on: 13th June 2019 , updated on: 14th June 2019

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