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