short seminar on mRNA granules with emphasis on stress granules

1. mRNA granules and gene expression
Advanced molecular biology course - HBKU
Dr Julie Decock, QBRI

2. mRNA granules
Composition, subcellular localisation, cell of origin, response to stimuli, function
Germ cell granules
Neuronal granules
Stress granules
Processing bodies
long term storage
Newbury SF et al, EMBO reports (2006) 7, 143-148.

3. mRNA granules
Germ cell granules
temporal 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.

4. Stress granules
Reprogramming of gene expression
global repression of protein translation
highest translational priority of stress-induced transcripts
Cellular stress
Heat shock
Oxidative stress
Environmental stress
Repair of stress-induced damage

5. Translation initiation shutoff
and polysome disassembly
Sequestration of mRNA
and mRNP aggregation
Stress
Mature Stress GranulesmRNA storage
mRNA decay
P-bodies
Nucleus
Translation reinitiation
and polysome reassembly
mRNA recovery
prokaryotes/eukaryotes
dynamic interplay with PB
Adapted from Dr M. Emara, QBRI

6. 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

7. Cell survival
Poly-adenylated circularized mRNA
translation 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

8. 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

9. Stress granules in cancer
Cancer = age-related disease
deregulated 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 stress
Hypoxia and formation of ROS
=> sequestration of pro-apoptotic factors

10. Stress granules in cancer
Stress granules play dual role in cancer treatment
pro-apoptotic :
binding of core components of the translation initiation complex => translation inhibition
induction 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.

11. 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

12. Thank you