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Spatio-temporal Dynamics and Mechanisms of Stress Granule Assembly.

Ohshima D, Arimoto-Matsuzaki K, Tomida T, Takekawa M, Ichikawa K - PLoS Comput. Biol. (2015)

Bottom Line: SGs were assembled as a result of applying arsenite to HeLa cells.This same distribution was also found in our experimental data suggesting the existence of multiple fusion steps in the SG assembly.Furthermore, we found that the initial steps in the SG assembly process and microtubules were critical to the dynamics.

View Article: PubMed Central - PubMed

Affiliation: Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Stress granules (SGs) are non-membranous cytoplasmic aggregates of mRNAs and related proteins, assembled in response to environmental stresses such as heat shock, hypoxia, endoplasmic reticulum (ER) stress, chemicals (e.g. arsenite), and viral infections. SGs are hypothesized as a loci of mRNA triage and/or maintenance of proper translation capacity ratio to the pool of mRNAs. In brain ischemia, hippocampal CA3 neurons, which are resilient to ischemia, assemble SGs. In contrast, CA1 neurons, which are vulnerable to ischemia, do not assemble SGs. These results suggest a critical role SG plays in regards to cell fate decisions. Thus SG assembly along with its dynamics should determine the cell fate. However, the process that exactly determines the SG assembly dynamics is largely unknown. In this paper, analyses of experimental data and computer simulations were used to approach this problem. SGs were assembled as a result of applying arsenite to HeLa cells. The number of SGs increased after a short latent period, reached a maximum, then decreased during the application of arsenite. At the same time, the size of SGs grew larger and became localized at the perinuclear region. A minimal mathematical model was constructed, and stochastic simulations were run to test the modeling. Since SGs are discrete entities as there are only several tens of them in a cell, commonly used deterministic simulations could not be employed. The stochastic simulations replicated observed dynamics of SG assembly. In addition, these stochastic simulations predicted a gamma distribution relative to the size of SGs. This same distribution was also found in our experimental data suggesting the existence of multiple fusion steps in the SG assembly. Furthermore, we found that the initial steps in the SG assembly process and microtubules were critical to the dynamics. Thus our experiments and stochastic simulations presented a possible mechanism regulating SG assembly.

No MeSH data available.


Related in: MedlinePlus

Simulation results of SG assembly.At 0 min, TIA1 (blue dots) distributed diffusely in the cytoplasm. At 6.7 min, several small SGs were assembled (red circles, one of which is indicated by a red arrowhead surrounded by white line). TIA2 (green dots, one of which is indicated by a green arrowhead), TIA3 (yellow dots, one on which is indicated by an yellow arrowhead), and TIA* (red dots, one of which is indicated by a red arrowhead) are also shown. At 16.7 min, SG distributed with no spatial preference. At 26.7 and 40 min, the size of SGs increased, and they gradually localized to the perinuclear region. At 60 min, the number of SG decreased, and the localization around nucleus became evident.
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pcbi.1004326.g004: Simulation results of SG assembly.At 0 min, TIA1 (blue dots) distributed diffusely in the cytoplasm. At 6.7 min, several small SGs were assembled (red circles, one of which is indicated by a red arrowhead surrounded by white line). TIA2 (green dots, one of which is indicated by a green arrowhead), TIA3 (yellow dots, one on which is indicated by an yellow arrowhead), and TIA* (red dots, one of which is indicated by a red arrowhead) are also shown. At 16.7 min, SG distributed with no spatial preference. At 26.7 and 40 min, the size of SGs increased, and they gradually localized to the perinuclear region. At 60 min, the number of SG decreased, and the localization around nucleus became evident.

Mentions: We ran SSs with an initial number of TIA1 equivalent to 9081 (blue dots at 0 min in Fig 4), which corresponded to a concentration of 100 nM in our 3D model cell. Each dot in Fig 4 indicates a single molecule with different colors for different molecular species. At 6.7 min, a small number of TIA2 (yellow dots, one of which is indicated by a yellow arrowhead) and TIA3 (green dots, one of which is indicated by a green arrowhead) were formed, and a small number of small SGs were also found (red circles, one of which is indicated by a red arrow surrounded by white line). TIA* containing TIA1 smaller than 12 are indicated by small red dots (one of which is indicated by a red arrowhead). At 16.7 min, both the number and the size of SGs increased. SGs gradually moved to perinuclear regions at later points in time (26.7, 40, and 60 min). These dynamics are clearly seen in the S2 Movie. Note that the number of TIA1 decreased with time as seen by the clearing up of blue dots from the background in the cytoplasmic space.


Spatio-temporal Dynamics and Mechanisms of Stress Granule Assembly.

Ohshima D, Arimoto-Matsuzaki K, Tomida T, Takekawa M, Ichikawa K - PLoS Comput. Biol. (2015)

Simulation results of SG assembly.At 0 min, TIA1 (blue dots) distributed diffusely in the cytoplasm. At 6.7 min, several small SGs were assembled (red circles, one of which is indicated by a red arrowhead surrounded by white line). TIA2 (green dots, one of which is indicated by a green arrowhead), TIA3 (yellow dots, one on which is indicated by an yellow arrowhead), and TIA* (red dots, one of which is indicated by a red arrowhead) are also shown. At 16.7 min, SG distributed with no spatial preference. At 26.7 and 40 min, the size of SGs increased, and they gradually localized to the perinuclear region. At 60 min, the number of SG decreased, and the localization around nucleus became evident.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482703&req=5

pcbi.1004326.g004: Simulation results of SG assembly.At 0 min, TIA1 (blue dots) distributed diffusely in the cytoplasm. At 6.7 min, several small SGs were assembled (red circles, one of which is indicated by a red arrowhead surrounded by white line). TIA2 (green dots, one of which is indicated by a green arrowhead), TIA3 (yellow dots, one on which is indicated by an yellow arrowhead), and TIA* (red dots, one of which is indicated by a red arrowhead) are also shown. At 16.7 min, SG distributed with no spatial preference. At 26.7 and 40 min, the size of SGs increased, and they gradually localized to the perinuclear region. At 60 min, the number of SG decreased, and the localization around nucleus became evident.
Mentions: We ran SSs with an initial number of TIA1 equivalent to 9081 (blue dots at 0 min in Fig 4), which corresponded to a concentration of 100 nM in our 3D model cell. Each dot in Fig 4 indicates a single molecule with different colors for different molecular species. At 6.7 min, a small number of TIA2 (yellow dots, one of which is indicated by a yellow arrowhead) and TIA3 (green dots, one of which is indicated by a green arrowhead) were formed, and a small number of small SGs were also found (red circles, one of which is indicated by a red arrow surrounded by white line). TIA* containing TIA1 smaller than 12 are indicated by small red dots (one of which is indicated by a red arrowhead). At 16.7 min, both the number and the size of SGs increased. SGs gradually moved to perinuclear regions at later points in time (26.7, 40, and 60 min). These dynamics are clearly seen in the S2 Movie. Note that the number of TIA1 decreased with time as seen by the clearing up of blue dots from the background in the cytoplasmic space.

Bottom Line: SGs were assembled as a result of applying arsenite to HeLa cells.This same distribution was also found in our experimental data suggesting the existence of multiple fusion steps in the SG assembly.Furthermore, we found that the initial steps in the SG assembly process and microtubules were critical to the dynamics.

View Article: PubMed Central - PubMed

Affiliation: Division of Mathematical Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Stress granules (SGs) are non-membranous cytoplasmic aggregates of mRNAs and related proteins, assembled in response to environmental stresses such as heat shock, hypoxia, endoplasmic reticulum (ER) stress, chemicals (e.g. arsenite), and viral infections. SGs are hypothesized as a loci of mRNA triage and/or maintenance of proper translation capacity ratio to the pool of mRNAs. In brain ischemia, hippocampal CA3 neurons, which are resilient to ischemia, assemble SGs. In contrast, CA1 neurons, which are vulnerable to ischemia, do not assemble SGs. These results suggest a critical role SG plays in regards to cell fate decisions. Thus SG assembly along with its dynamics should determine the cell fate. However, the process that exactly determines the SG assembly dynamics is largely unknown. In this paper, analyses of experimental data and computer simulations were used to approach this problem. SGs were assembled as a result of applying arsenite to HeLa cells. The number of SGs increased after a short latent period, reached a maximum, then decreased during the application of arsenite. At the same time, the size of SGs grew larger and became localized at the perinuclear region. A minimal mathematical model was constructed, and stochastic simulations were run to test the modeling. Since SGs are discrete entities as there are only several tens of them in a cell, commonly used deterministic simulations could not be employed. The stochastic simulations replicated observed dynamics of SG assembly. In addition, these stochastic simulations predicted a gamma distribution relative to the size of SGs. This same distribution was also found in our experimental data suggesting the existence of multiple fusion steps in the SG assembly. Furthermore, we found that the initial steps in the SG assembly process and microtubules were critical to the dynamics. Thus our experiments and stochastic simulations presented a possible mechanism regulating SG assembly.

No MeSH data available.


Related in: MedlinePlus