Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

Park, Ye Jin; Choi, Dong Wook; Cho, Sang Woo; Han, Jaeseok; Yang, Siyoung; Choi, Cheol Yong

doi:10.3390/ijms21155360

Cited by 33 publications

(26 citation statements)

References 52 publications

(63 reference statements)

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“…For example, the major difference in SG composition between an acute oxidative stress induced by sodium arsenite and a chronic nutrient starvation stress is the exclusion of RACK1 from chronic SGs ( Reineke et al, 2018 ). This is significant because RACK1 recruitment to SGs is essential for inhibition of the mitogen-activated protein kinase (MAPK) pathway, preventing cell apoptosis and promoting cell survival ( Arimoto et al, 2008 ; Reineke et al, 2018 ; Park et al, 2020 ). However, it is unclear whether this change in composition is due to stress duration as suggested, or whether it is due to differences in stress type, as specific stresses can also induce non-canonical SGs.…”

Section: Introductionmentioning

confidence: 99%

The Integral Role of RNA in Stress Granule Formation and Function

Campos-Melo

Hawley

Droppelmann

et al. 2021

Front. Cell Dev. Biol.

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Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures. With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases. In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

The Integral Role of RNA in Stress Granule Formation and Function

Campos-Melo

Hawley

Droppelmann

et al. 2021

Front. Cell Dev. Biol.

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“…Moreover, mutations in TDP-43 led to a significant reduction in SG formation and increased apoptosis in human fibroblasts (Orrù et al, 2016). SGs suppress ROS generation (Takahashi et al, 2013) and attenuate RACK1 (Park et al, 2020), which may be part of the mechanism for apoptosis inhibition. Another possible role of SGs under OS may involve the elimination of damaged cellular macromolecules including oxidized RNA, which will be discussed below.…”

Section: Stress Granules and Their Role In Cellular Functions And Human Diseasesmentioning

confidence: 99%

Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1

Alluri

McCrae

2021

Front. Mol. Biosci.

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Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNAs, containing inverted repeat (IR) Alus in 3′ UTRs, AU-rich elements, and RNA-binding proteins. SGs and processing bodies (P-bodies) transiently interact through a docking mechanism to allow the exchange of RNA species. However, the types of RNA species exchanged, and the mechanisms and outcomes of exchange are still unknown. Specialized RNA-binding proteins, including adenosine deaminase acting on RNA (ADAR1-p150), with an affinity toward inverted repeat Alus, and Tudor staphylococcal nuclease (Tudor-SN) are specifically recruited to SGs under OS along with an RNA transport protein, Staufen1 (STAU1), but their precise biochemical roles in SGs and SG/P-body docking are uncertain. Here, we critically review relevant literature and propose a hypothetical mechanism for the processing and decay of oxidized-RNA in SGs/P-bodies, as well as the role of ADAR1-p150, Tudor-SN, and STAU1.

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“…The proteasome inhibitor bortezomib triggers HRI-dependent SG formation, and HRI knockout prevents the induction of SGs and increases bortezomib-mediated apoptosis [62]. Moreover, the cytotoxic drug morusin activates PKR-dependent SG formation, and both PKR inhibition and G3BP1 knockout impair SG assembly and enhance morusin cytotoxic effect in cancer cells [63]. Lapatinib, a tyrosine kinase inhibitor, induces PERK-mediated SG assembly, and PERK silencing sensitizes breast cancer cell lines to lapatinib-induced cell death [64].…”

Section: Open Accessmentioning

confidence: 99%

Cancer cell adaptability: turning ribonucleoprotein granules into targets

et al. 2021

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Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. RNP granules between stress and translationRegulating the expression of the genomic information is crucial to ensure cell identity and functionality. During transformation into cancer cells and throughout tumor progression, cells dynamically modulate the expression of their genomic information to adapt to environmental cues. Control of mRNA translation ensures the spatiotemporal adjustment of protein synthesis, and is often dysregulated in cancer cells to favor their adaptability [1]. In particular, regulation of translation initiation allows cancer cells to reprogram this activity towards essential mRNAs, such as those encoding oncogenes, to facilitate cell growth, proliferation, and survival [2]. Moreover, cancer cells must adapt to stress conditions in the TME, mainly through activation of the integrated stress response (ISR) [3,4] (Figure 1). This pathway controls translation initiation through eukaryotic initiation factor 2 (eIF2), which, once phosphorylated on its α subunit, prevents the formation of the ternary complex (eIF2:GTP: methionyl-initiator-tRNA) and consequently blocks translation initiation [5]. Four stress-sensor kinases can induce eIF2α phosphorylation, namely the PKR-like endoplasmic reticulum kinase (PERK), general control nonrepressible 2 (GCN2), heme-regulated inhibitor (HRI), and protein kinase R (PKR). The outcome of ISR activation is a global decrease in protein synthesis, while sparing the translation of some specific mRNAs such as that of transcription factor ATF4 [4]. Activation of this pathway, and the resulting selective translation, favor tumor progression following endoplasmic reticulum stress caused for instance by the hypoxic TME [6]. Furthermore, ISR activation by aberrant MYC expression enables cancer cells to adapt to this intrinsic stress by reprogramming translational programs. Consequently, the ISR prevents cancer cells from entering apoptosis and promotes both tumor progression [7,8] and escape from antitumor immunity [9,10].

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Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

Cited by 33 publications

References 52 publications

The Integral Role of RNA in Stress Granule Formation and Function

The Integral Role of RNA in Stress Granule Formation and Function

Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1

Cancer cell adaptability: turning ribonucleoprotein granules into targets

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