P‐body‐induced inactivation of let‐7a miRNP prevents the death of growth factor‐deprived neuronal cells

Patranabis, Somi; Bhattacharyya, S. N.

doi:10.1096/fj.201700633r

Cited by 8 publications

(11 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This results in the release of Let-7a miRNA from AGO2 and subsequent activation of Let-7a target KRAS leading to neuronal differentiation. Ectopic expression of P-body proteins, AGO2 or GW182 was sufficient to induce differentiation pointing to a direct link between miRISC activity and cell fate decisions (Patranabis and Bhattacharyya, 2018). An important role of miRISC was recently described in the regulation of the quiescent state in adult neuronal stem cells (Katz et al, 2016).…”

Section: Neurogenesis and Differentiationmentioning

confidence: 99%

“…Reversibility of miRNA mediated translation repression is likely to happen in all kinds of cells during the growth, division, differentiation or in response to stress and external cues (Bhattacharyya et al, 2006;Jafarifar et al, 2011;Bellon et al, 2017;Patranabis and Bhattacharyya, 2018). This mechanism is particularly apt for neurons where compartmentalized and cue dependent translation is evolved to a great extent.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

show abstract

Section: Neurogenesis and Differentiationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…P-bodies comprise of several RNA degrading enzymes and are known to host repressed mRNAs which respond to cellular stress and mobilize reversibly from translating polysomes to P-bodies and vice versa. The miRNA effector protein Ago2 has also been reported to localize inside cytoplasmic P-bodies under certain circumstances (Filipowicz et al, 2008;Patranabis and Bhattacharyya, 2018).…”

Section: Proteomic Analysis and Functional Studies Have Identified A mentioning

confidence: 99%

“…We also noted an uncoupling of miR-122 from Ago2 in presence of LDs. This can be attributed to certain modifications such as phosphorylation (Patranabis and Bhattacharyya, 2016;Patranabis and Bhattacharyya, 2018) of Ago2 happening at the Pbody-LD interface. Uncoupling of miR-122 from Ago2 might also be due to the presence of some unidentified RNA binding proteins on the LD surface that have a higher affinity for miR-122 and thus, shifts the equilibrium from Ago2-miR-122 interaction to the miRNA free Ago2 population-a process which may also be accelerated by miRNA-binder HuR that reversibly binds miRNA (Mukherjee et al, 2016) to facilitate this phase separation.…”

Section: Proteomic Analysis and Functional Studies Have Identified A mentioning

confidence: 99%

Lipid Droplets Promote Phase Separation of Ago2 to Accelerate Dicer1 Loss and Decelerate miRNA Activity in Lipid Exposed Hepatic Cells

Bandopadhyay

Basu

Mukherjee

et al. 2020

Preprint

View full text Add to dashboard Cite

miR-122 is a liver specific miRNA that plays an important role in controlling metabolic homeostasis in mammalian liver cells. Interestingly, miR-122 on exposure to lipotoxic stress is reduced in liver cells. To fight stress, miRNA processor Dicer1 is depleted to cause reduced miR-122 production and the lowering of miRNA level ensures a better stress response in hepatocytes under lipotoxic stress. Interestingly, lipid droplets, formed in the liver cells on exposure to high fat, ensure cytoplasmic phase separation of Ago2 and prevent interaction of Ago2 with Dicer1. Lipid droplets bind miRNA and enhance miRNA-Ago2 uncoupling and Ago2 phase separation. Loss of interaction between Ago2 and Dicer1 eventually facilitates export and lowering of cellular Dicer1, a process also dependent on the endosomal maturation controller protein Alix, thereby ceasing pre-miRNA processing by Dicer1 in lipid exposed cells. Depletion of lipid droplets by downregulation of Perilipins with siRNAs resulted in a rescue of cellular Dicer1 level and Ago2-Dicer1 interaction. This is a novel mechanism that liver cells adopt to restrict cellular miRNA levels under stress condition. Thus, lipid droplets prevent cell death upon exposure to high fat by reducing intra and extracellular pool of miR-122 in hepatic tissue.

show abstract

“…RNA processing bodies are considered as the subcellular structures responsible for reversible storage of miRNA-repressed messages and depletion of P-bodies (PBs) is associated with relocalization of the repressed messages to translating polysomes and thus considered as the key mechanism for reversible regulation of repressive activity of miRNAs (Bhattacharyya et al 2006). In neuronal context, storage of Ago2 to PBs is considered as the prerequisite for reversal of miRNA activity during growth factor withdrawn and essential for neuronal survival (Patranabis and Bhattacharyya 2018).…”

Section: Introductionmentioning

confidence: 99%

Amyloid Beta Oligomers Prevents Lysosomal Targeting of miRNP to Stop Its Recycling and Target Cytokine Repression in Glial Cells

Bhattacharyya

2020

Preprint

View full text Add to dashboard Cite

AbstractmRNAs encoding inflammatory cytokines are targeted by miRNAs and remain repressed in neuroglial cells. On exposure to amyloid beta 1-42 oligomers, glial cells start expressing proinflammatory cytokines although there has been increase in repressive miRNAs levels as well. Exploring the mechanism of this potential immunity of target cytokine mRNAs against repressive miRNAs in amyloid beta exposed glial cells, we have identified differential compartmentalization of repressive miRNAs in glial cells to explain this aberrant miRNA function. While the target mRNAs were found to be associated with polysomes attached to endoplasmic reticulum, the miRNPs found to be present predominantly with endosomes that failed to recycle to endoplasmic reticulum attached polysomes to repress mRNA targets in treated cells. Amyloid beta oligomers, by masking the Rab7 proteins on endosomal surface, affects Rab7 interaction with Rab Interacting Lysosomal Protein (RILP) on lysosomes to restrict endosomal maturation and its lysosomal targeting. This causes retarded miRNP targeting to lysosomes and recycling. Similar defects in miRNP retrieval has been observed in endosome maturation defective cells depleted for RILP or treated with Bafilomycin. RNA processing body localization of the miRNPs was also noted in treated cells that happens as a consequence of enhanced endosomal retention of miRNPs. Interestingly, depletion of P-body partly rescues the miRNA function in glial cells exposed to amyloid beta and restricts the excess cytokine expression there.Graphical AbstractKey PointsAmyloid beta exposure causes accumulation of inactive miR-146 miRNP to cause elevated proinflammatory cytokine production in glial cells.Amyloid beta masks Rab7-RILP interaction to reduce endosome lysosome interaction.Accumulated miRNPs failed to get targeted to lysosomes in amyloid exposed cells due to loss of endosome lysosome interactionLysosomal compartmentalization of miRNPs is required for its recycling and repression of de novo targetsAccumulated miRNPs are stored in P-Bodies and depletion of P-Bodies rescues miRNA function in amyloid exposed glial cells.

show abstract

P‐body‐induced inactivation of let‐7a miRNP prevents the death of growth factor‐deprived neuronal cells

Cited by 8 publications

References 43 publications

The Role of Dynamic miRISC During Neuronal Development

The Role of Dynamic miRISC During Neuronal Development

Lipid Droplets Promote Phase Separation of Ago2 to Accelerate Dicer1 Loss and Decelerate miRNA Activity in Lipid Exposed Hepatic Cells

Amyloid Beta Oligomers Prevents Lysosomal Targeting of miRNP to Stop Its Recycling and Target Cytokine Repression in Glial Cells

Contact Info

Product

Resources

About