Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly.
The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in the mRNA metabolism. The absence of FMRP in neurons leads to alterations of the synaptic plasticity, probably as a result of translation regulation defects. The exact molecular mechanisms by which FMRP plays a role in translation regulation have remained elusive. The finding of an interaction between FMRP and the RNA interference silencing complex (RISC), a master of translation regulation, has suggested that both regulators could be functionally linked. We investigated here this link, and we show that FMRP exhibits little overlap both physically and functionally with the RISC machinery, excluding a direct impact of FMRP on RISC function. Our data indicate that FMRP and RISC are associated to distinct pools of mRNAs. FMRP, unlike RISC machinery, associates with the pool of mRNAs that eventually goes into stress granules upon cellular stress. Furthermore, we show that FMRP plays a positive role in this process as the lack of FMRP or a point mutant causing a severe fragile X alter stress granule formation. Our data support the proposal that FMRP plays a role in controlling the fate of mRNAs after translation arrest.
Didiot
Marie-Cécile
MC
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université Louis Pasteur, Collège de France, Chaire de Génétique Humaine, Illkirch-Graffenstaden, France.
Subramanian
Murugan
M
Flatter
Eric
E
Mandel
Jean-Louis
JL
Moine
Hervé
H
D000818:Animals; D060565:Argonaute Proteins; D003594:Cytoplasmic Granules / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017354:Point Mutation; D011247:Pregnancy; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*; D013312:Stress, Physiological
D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D051860:Fragile X Messenger Ribonucleoprotein 1; D020033:Protein Isoforms; D012333:RNA, Messenger; D034743:RNA-Induced Silencing Complex; C466422:AGO2 protein, human