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Leading Edge

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Not Going with the Flow:
How Cells Adapt Internal Physics
Hector Garcia-Seisdedos,1,2 Meta Heidenreich,1,2 and Emmanuel D. Levy1,*
1Department of Structural Biology, Weizmann Institute of Science, Rehovot, 7610001, Israel
2These authors contributed equally
*Correspondence: emmanuel.levy@weizmann.ac.il
https://doi.org/10.1016/j.cell.2020.11.021

Defining the principles underlying the organization of biomolecules within cells is a key challenge of current
cell biology research. Persson et al. now identify a powerful layer of regulation that allows cells to decouple
diffusion from temperature by modulating their intracellular viscosity. This so-called viscoadaptation is medi-
ated through trehalose and glycogen activities, which alter diffusion dynamics and self-assembly propensity
inside the cell globally.

A yeast cell resuming growth, a fertilized
egg’s first division, or a human cell under-
going a cancerous transformation are all
life processes that rely on an intricate
interplay between biomolecules. Our abil-
ity to characterize and understand these
events has gone hand-in-hand with the
advent of technologies for profiling cells’
molecular infrastructure in terms of their
RNA, protein, lipid, and metabolite con-
tent. These technologies provide informa-
tion on a cell’s biomolecular building
blocks but do not probe the physical envi-
ronment in which these building blocks
function. For example, while the tran-
scriptomic response of a yeast cell to a
heat shock has been known for two de-
cades (Gasch et al., 2000), only in recent
years have we begun to grasp the
comprehensive molecular and biophysi-
cal mechanisms of this response. Today,
we know that it involves a complex inter-
play between the global modulation of
intracellular biophysics and specific
changes in protein structure, localization,
and assembly (Iserman et al., 2020; Trian-
dafillou et al., 2020). Persson et al. now
unveil a new dimension of this response,
and of adaptation in general, whereby
cells adjust their intracellular environment
to maintain constant diffusion rates
despite changes in temperature (Persson
et al., 2020).
First, the authors examined how tem-
perature changed the diffusion rates of
molecules in the cytoplasm, in vivo, and
after cell lysis, in vitro. To this end, they
monitored a biotinylation reaction be-
tween the enzyme BirA and a green fluo-
rescent protein (GFP) harboring a BirA
recognition tag. The fraction of bio-
tinylated GFP enabled the assessment
of viscosity, as the biotinylation rate was
diffusion limited. In cell lysates, the au-
thors observed that the diffusion dy-
namics increased with temperature, as
expected. In contrast, the fraction labeled
with GFP was independent of tempera-
ture in vivo. Furthermore, right after the
heat shock, diffusion increased in vivo
and in vitro, as measured by fluorescence
recovery after photobleaching (FRAP).
However, only in vivo was this faster diffu-
sion followed by a progressive slowdown.
This indicates that cells were compen-
sating for the rise in thermal motions by
increasing their intracellular viscosity, a
mechanism the authors termed viscoa-
daptation.
Persson et al. sought to investigate the
molecular mechanisms underpinning vis-
coadaptation to heat shock. Inhibiting
translation did not prevent viscoadapta-
tion, suggesting it is independent of pro-
tein biosynthesis. Interestingly, a potential
mechanism was suggested by literature
indicating that heat shock induces pro-
duction of trehalose and glycogen in cells.
Indeed, yeast cells failed to viscoadapt to
heat shock when trehalose and glycogen
synthesis was inhibited genetically or
pharmacologically (Figure 1A).
Nutrient starvation is also known to
prompt trehalose and glycogen synthesis.
This upregulation, too, is linked to viscoa-
daptation, as viscosity increased in
starved cells, and less so in strains unable
to synthesize trehalose and glycogen.
To dissect the role of the two carbohy-
drates, solutions containing increasing
concentrations of either or both sugars
were analyzed. As expected, increasing
their concentration made the solution
more viscous, yet both sugars showed
distinct and synergistic properties. While
a trehalose-rich drop of water quickly so-
lidified, the addition of glycogen inhibited
this process and maintained the solution
in a gel-like state. In turn, the solubility of
GFP was limited in a glycogen-rich solu-
tion and partially restored by the addition
of trehalose.
Given that trehalose and glycogen
impact protein solubility, they might also
modulate protein interactions, self-as-
sembly, and aggregation. Indeed, lysates
of heat-shocked cells showed protein in-
clusions that were absent in knockout
strains unable to synthesize both carbo-
hydrates. Conversely, increasing both
sugars’ production led to a larger fraction
of immobile and, presumably, insoluble
intracellular GFP. Functional assemblies
were also affected by viscoadaptation,
albeit in the opposite manner. The pro-
duction of glycogen and trehalose in-
hibited stress granule formation, implying
that viscoadaptation could act as a gen-
eral modulator of phase separation.
Temperature and nutrient availability
are both coupled to intracellular ATP
levels, which may provide a cue for vis-
coadaptation. Indeed, decreased ATP
levels increased intracellular viscosity in
a trehalose-glycogen-dependent manner.
The authors conducted FRAP experi-
ments with a fluorescence-based ATP

1462 Cell 183, December 10, 2020 ª 2020 Elsevier Inc.

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cellular biophysics, and the cell machin-

ery, much work will be needed to fully
grasp how cells navigate these dimen-
sions to ultimately reveal life in all of its
molecular details.

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