Science - 31 January 2020

INSIGHTS | PERSPECTIVES

sciencemag.org SCIENCE

PHOTO: LEE

ET AL

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)

phase separation but do not
lead to a fixed position or stoi-
chiometry of the components
within the organelle, unlike in
a classical protein complex ( 2 ).
Current models posit that P-
bodies store messenger RNAs
(mRNAs) that are not actively
translated, whereas stress gran-
ules serve a similar purpose
but only form when a stress re-
presses translation.
Membrane contact sites are
established and maintained by
protein complexes that tether
two membranes stably and
keep organelles in proximity for
hours. Lee et al. found that most
of the interactions between the
ER and P-bodies or stress gran-
ules are stable, akin to mem-
brane contact sites. This raises
numerous questions. What is
the molecular nature of the
tethering between the ER and
membraneless organelles? One
possibility is that liquid drop-
lets attach to the ER through
translating mRNAs and ribo-
somes bound to the ER surface. However, P-
bodies and stress granules appear to repress
translation and exclude ribosomes. Further-
more, inhibition of ER translation did not
detach P-bodies from the ER. Therefore, the
specific nature of the interactions between
ER tubules and P-bodies or stress granules
implies the existence of a dedicated ma-
chinery, currently unknown, that serves as
molecular glue between these structures.
What is the role of attaching RNA-con-
taining membraneless organelles to the
ER? Connection between the ER and P-
bodies seems to be evolutionary conserved
from yeast to mammals ( 5 , 6 ). Moreover, in
yeast, the nucleolus is tethered to the ER-
derived nuclear membrane ( 4 , 7 ). Although
their physiological role is unclear, the evo-
lutionary conservation of contacts between
ER and membraneless organelles suggests
that this is important. Organelle tethering
is largely considered to create a platform
that allows the exchange of metabolites
and information. For example, the proxim-
ity between organelles allows transport-
ers to shuttle hydrophobic lipid molecules
from one membrane to the other through
the hydrophilic cytosol. Organelle proxim-
ity also allows exchange of calcium ions
from one compartment (for example, the
ER) to another (for example, mitochon-
dria), with minimal disturbance of cyto-
solic calcium concentration ( 1 ). Because
substantial translation occurs at the ER
and because P-bodies and stress granules

can be sites of mRNA storage, Lee et al.

speculated that these connections serve to

exchange mRNAs from the droplet, where

they are translationally silent, to their site

of expression on the ER. However, the P-

body and stress granule transcriptomes ( 5 ,

6 , 8 ) are not obviously enriched in mRNAs

that are destined to be translated at the

ER (that is, mRNAs encoding secreted pro-

teins). Future experiments will likely re-

veal whether such mRNAs are enriched in

droplets attached to the ER; whether teth-

ering facilitates the transition from trans-

lationally silent to active, and vice versa;

and whether specific regulatory processes

govern the handover of mRNAs from P-

bodies to ER according to cellular needs.

An interesting observation by Lee et al.

unveils one potential role of the ER-drop-

let tether: Liquid droplets undergo divi-

sion at sites where ER tubules are present.

This parallels the previous discovery by the

same laboratory that the sites of division

for two membrane-bound organelles, the

endosomes and the mitochondria ( 9 , 10 ),

are also characterized by the nearby pres-

ence and perhaps tethering of ER tubules.

This suggests that contacting the ER is a

prerequisite for liquid droplets to split.

Conventional liquid droplets do not split

spontaneously. However, in the dynamic

cytoplasm, could ER motion simply apply

mechanical forces onto membraneless or-

ganelles, causing their division? Mechani-

cal forces appear to be an important factor

in deciding where and when

mitochondrial division take

place. Actin filaments nucle-

ated at the ER were shown to

be particularly important for

mitochondrial fission ( 11 ), and

mechanical forces are sufficient

to cause this phenomenon ( 12 ).

It is thus conceivable that the

ER-nucleated actin filaments

could forcibly divide mem-

braneless organelles. Alterna-

tively, the surface of the ER

membrane may act like a sur-

factant that helps to disperse

membraneless organelles. The

ER membrane is charged, and

specific ER-localized proteins

might influence local ionic

strength, which could trig-

ger local dissolution of liquid

droplets. Or, perhaps the ER

recruits a specific division ma-

chinery. Because division of a

liquid droplet requires energy,

candidate fission enzymes

include adenosine triphos-

phatases (ATPases) such as mo-

lecular chaperones or members

of the DEAD-box family ( 13 , 14 ), which are

enriched in P-bodies and stress granules.

As for mitochondria and endosomes, the

advantage of making droplet fission coincide

with the ER is unknown and requires further

investigation. Does it prevent membraneless

organelles from getting entangled with the

ER? Or, perhaps the ER is involved in con-

trolling droplet numbers for other reasons.

To answer these questions, it will be essential

to uncover the molecular machines that con-

nect the ER to P-bodies and stress granules

and mediate organelle fission. j

REFERENCES AND NOTES

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2. A. A. Hyman et al., Annu. Rev. Cell Dev. Biol. 30 , 39
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3. J. E. Lee et al., Science 367 , eaay7108 (2020).


4. C. P. Brangwynne et al., Proc. Natl. Acad. Sci. U.S.A. 108 ,
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5. C. Wang et al., eLife 7 , e29815 (2018).


6. C. Kilchert et al.,Mol. Biol. Cell 21 , 2624 (2010).


7. K. Mekhail et al., Nature 456 , 667 (2008).


8. A. Hubstenberger et al., Mol. Cell 68 , 144 (2017).


9. M. J. Hoyer et al., Cell 175 , 254 (2018).


10. J. R. Friedman et al., Science 334 , 358 (2011).


11. F. Korobova et al., Science 339 , 464 (2013).


12. S. C. J. Helle et al., eLife 6 , e30292 (2017).


13. M. Hondele et al., Nature 573 , 144 (2019).


14. S. Jain et al., Cell 164 , 487 (2016).

ACKNOWLEDGMENTS

B.K. is an investigator of the Wellcome Trust (grant

214291/Z/18/Z). K.W. is supported by the Swiss National

Science Foundation (project number 31003A_179275). The

authors thank E. Dufresne for discussions on droplet behavior.

10.1126/science.aba3771

In human cells, the endoplasmic reticulum (red) forms stable contacts with stress

granules (green) and processing bodies (P-bodies; not shown).

508 31 JANUARY 2020 • VOL 367 ISSUE 6477

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