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mRNA granules and gene expression
Advanced molecular biology course - HBKUDr Julie Decock, QBRI
mRNA granules
Composition, subcellular localisation, cell of origin, response to stimuli, function
Germ cell granulesNeuronal granules
Stress granulesProcessing bodies
long term storage
Newbury SF et al, EMBO reports (2006) 7, 143-148.
mRNA granules
Germ cell granulestemporal and spatial activation of maternal mRNA during early embryogenesis
Neuronal granules transport and translation of mRNA from the soma into the dendrites => synaptic plasticity, habituation and memory
Susan Strome, UCSC
Weill L et al, Nat. Struct. Mol. Biol. 2012; 19: 577–585.
Stress granules
Reprogramming of gene expressionglobal repression of protein translation
highest translational priority of stress-induced transcripts
Cellular stress
Heat shock
Oxidative stress
Environmental stress
Repair of stress-induced damage
Translation initiation shutoff and polysome disassembly
Sequestration of mRNAand mRNP aggregation
Stress
Mature Stress GranulesmRNA storage
mRNA decayP-bodies
Nucleus
Translation reinitiation and polysome reassembly
mRNA recovery
prokaryotes/eukaryotesdynamic interplay with PB
Adapted from Dr M. Emara, QBRI
Translation initiation shutoff and polysome disassembly
Anderson and Kedersha, JCS 2002; 115: 3227-3234.
phosphorylation of eIF2a
Inhibition of eIF2B+
binding of TIA to inactive 48S preinitiation complex
self-aggregation of TIA-1
stress granules
eIF2B charges preinitiation complex with GTP
Assembly of 48S preinitiation complex on capped transcript
Scanning and binding of tRNA to initiation codon
Assembly of ribosomes and polysomes
Cell survival
Poly-adenylated circularized mRNAtranslation initiation complex (eIF4E, eIF4G, eIF3, peIF2, 40S, eIF2B)
RNA binding proteins (PABP, TIA-1, TIAR)mRNA (de)stabilizing proteins (TPP, HuR)
Housekeeping genes (GAPDH)TF, signalling molecules, helicases,
…
Mature Stress Granules
Stress granules in viral infection
West Nile Virus (ss +RNA virus)
The virus -RNA strand binds TIAR/TIA-1, inhibiting the formation of stress granules and preventing the cell from shutting down translation.
Emara MM et al, PNAS 2007; 104(21): 9041–9046.
avoid sequestration of own mRNA in translationally
silenced mRNPs
Stress granules in cancer
Cancer = age-related diseasederegulated expression of RNA binding proteins over time, eg HuR
=> stabilisation of mRNA transcripts involved in cell cycle progression, apoptosis, invasion, metastasis, cell migration, adhesion
Tumor progression induces oxidative stressHypoxia and formation of ROS
=> sequestration of pro-apoptotic factors
Stress granules in cancer
Stress granules play dual role in cancer treatment
pro-apoptotic : binding of core components of the translation initiation complex => translation inhibitioninduction of ROS production => ER stress
therapy resistance : sequestration/inactivation of pro-apoptotic proteins (eg. RACK1, TRAF2)storage/stabilisation and bulk release of anti-apoptotic proteins (eg. p21)
Kaehler C et al, Nucleic Acids Res. 2014; 42(10): 6436–6447.
Stress granules in neurodegenerative diseases
Amyotrophic Lateral Sclerosis (ALS)loss of upper/lower motor neurons
frontotemporal dementia (FTLD) atrophy in frontal/temporal lobe
Alzheimer disease (AD)Loss of neuron communication (Tau tangles), amyloid plaques
TDP-43 mutations
mutations in Tau, TDP-43, FUS
mutations in Tau
Aulas A et al; Molecular Neurodegeneration 2012, 7:1.
Mutations in RNA binding proteins
disruption of stress responsive SG assembly => halted translation of
stress-response proteins
Thank you