RhoA/ROCK1 signaling regulates stress granule formation and apoptosis

Tsai, Nien Pei; Li, Wei

doi:10.1016/j.cellsig.2009.12.001

Cited by 101 publications

(86 citation statements)

References 24 publications

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“…Our results indicate that the pathological mutant handles stress in a manner markedly different from that of the wild type; these differences will be explored in future studies in order to understand how pathological TDP-43 mutants contribute to neurodegeneration and cell death. It has been suggested that the formation of stress granules delays apoptosis by sequestering proapoptotic factors (such as RACK1 and ROCK1) (8,31,71). Our observation that cells recover after an initial stress response is compatible with this model.…”

Section: Discussionsupporting

confidence: 80%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

299

306

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TDP-43, or TAR DNA-binding protein 43, is a pathological marker of a spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinpositive inclusions. TDP-43 is an RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation. Recent work also suggests that TDP-43 associates with cytoplasmic stress granules, which are transient structures that form in response to stress. In this study, we establish sorbitol as a novel physiological stressor that directs TDP-43 to stress granules in Hek293T cells and primary cultured glia. We quantify the association of TDP-43 with stress granules over time and show that stress granule association and size are dependent on the glycine-rich region of TDP-43, which harbors the majority of pathogenic mutations. Moreover, we establish that cells harboring wild-type and mutant TDP-43 have distinct stress responses: mutant TDP-43 forms significantly larger stress granules, and is incorporated into stress granules earlier, than wild-type TDP-43; in striking contrast, wild-type TDP-43 forms more stress granules over time, but the granule size remains relatively unchanged. We propose that mutant TDP-43 alters stress granule dynamics, which may contribute to the progression of TDP-43 proteinopathies.TAR DNA-binding protein 43 (TDP-43) is a highly conserved, ubiquitously expressed RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family (11,47,73). TDP-43 and other hnRNPs are multifunctional proteins that regulate gene expression in both the nucleus and the cytoplasm (47, 75). In the nucleus, TDP-43 binds singlestranded DNA and RNA (10,11,19,20,49,62) and can function as both a transcriptional repressor (1, 2, 62) and a splicing modulator (15,17,20,55). Specifically, TDP-43 regulates pre-mRNA splicing by binding mRNA with (UG) 6-12 sequences (19) and by recruiting other hnRNP proteins into repressive splicing complexes (10,18,55). However, as a nucleocytoplasmic shuttling protein (12), TDP-43 also has distinct cytoplasmic functions, including mRNA stabilization (74).Recent studies indicate that TDP-43 localizes to stress granules (SGs) in response to heat shock, oxidative stress, and chemical inducers of stress (23,33). SGs are dynamic cytoplasmic structures that are believed to act as sorting stations for mRNAs (5). SG composition and morphology differ according to stress and cell type (5, 39), but some core components are conserved. These core components include the RNA-binding protein TIAR (TIA-1 cytotoxic granule-associated RNA-binding protein-like 1) and the stalled translation initiation complex components eIF3 and eIF4G (44,45). In contrast, the incorporation of the RNA-binding proteins HuR and hnRNP A1 into SGs differs with the cell type and stress (5, 39). The physiological stressors that cause TDP-43 aggregates and SGs to form-and the cells in which this occurs-remain unresolved. Moreover, very little is known about the function of cytoplasmic TDP-43, a press...

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Section: Discussionsupporting

confidence: 80%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

299

306

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“…Rho-associated protein kinase 1 (Rock1) links SG formation to cell survival (Tsai and Wei, 2010). Thus, sequestration of Rock1 is one of the mechanisms that contribute to the antiapoptotic function of SGs.…”

Section: Ampk Activation Reorganizes Microtubules In Stressedmentioning

confidence: 99%

AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

2016

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Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 59-AMPactivated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic conditions. Here, we dissected the role of AMPK for oxidant-induced SG formation. Our studies identified multiple steps of de novo SG assembly that are controlled by the kinase. Single-cell analyses demonstrated that pharmacological AMPK activation prior to stress exposure changed SG properties, because the granules became more abundant and smaller in size. These altered SG characteristics correlated with specific changes in cell survival, cell signaling, cytoskeletal organization, and the abundance of translation initiation factors. Specifically, AMPK activation increased stress-induced eukaryotic initiation factor (eIF) 2a phosphorylation and reduced the concentration of eIF4F complex subunits eIF4G and eIF4E. At the same time, the abundance of histone deacetylase 6 (HDAC6) was diminished. This loss of HDAC6 was accompanied by increased acetylation of a-tubulin on Lys40. Pharmacological studies further confirmed this novel AMPK-HDAC6 interplay and its importance for SG biology. Taken together, we provide mechanistic insights into the regulation of SG formation. We propose that AMPK activation stimulates oxidant-induced SG formation but limits their fusion into larger granules.

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“…All these data together suggest that ETS-1 plays an essential role in the S1P-stimulated CD44 expression and chemotaxis. S1P 3 /ROCK1 Signaling Up-regulates ETS-1 via the JNK/cJun Pathway-It has been shown that JNK is a downstream signaling molecule of ROCK1 (55)(56)(57). Also, promoter analysis found four candidate binding sites of AP-1 (a heterodimeric complex composed of proteins including c-Jun and c-Fos) transcriptional factor in the ETS-1 promoter region (found in a EpiTect ChIP qPCR Primers search at the SABiosciences website).…”

Section: Ets-1 Plays An Essentialmentioning

confidence: 99%

ETS-1-mediated Transcriptional Up-regulation of CD44 Is Required for Sphingosine-1-phosphate Receptor Subtype 3-stimulated Chemotaxis

Zhang

Lee

Gartung

et al. 2013

Journal of Biological Chemistry

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Background: S1P 3 -mediated chemotaxis plays a pivotal role in various physiological and pathophysiological activities. Results: S1P/S1P 3 signaling activates ROCK/JNK/ETS-1/CD44 pathway, and inhibition of this pathway abrogates S1P 3 -stimulated chemotaxis. Conclusion: ETS-1/CD44 signaling mediates S1P/S1P 3 -regulated chemotaxis. Significance: Therapeutically manipulating S1P 3 -mediated chemotaxis requires a molecular understanding of its regulated signaling pathway.

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RhoA/ROCK1 signaling regulates stress granule formation and apoptosis

Cited by 101 publications

References 24 publications

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

ETS-1-mediated Transcriptional Up-regulation of CD44 Is Required for Sphingosine-1-phosphate Receptor Subtype 3-stimulated Chemotaxis

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