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Published online May 19, 2008
doi:10.1083/jcb.200708004
The Journal of Cell Biology, Vol. 181, No. 4, 639-653
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Kawahara et al.
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Article

 Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP

Hironori Kawahara1, Takao Imai1, Hiroaki Imataka2, Masafumi Tsujimoto3, Ken Matsumoto3, and Hideyuki Okano1,4

1 Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
2 Genomic Sciences Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
3 Laboratory of Cellular Biochemistry, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
4 Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Correspondence to Hideyuki Okano: hidokano{at}sc.itc.keio.ac.jp

Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural stem cells. We previously reported that Msi1 contributes to the maintenance of the immature state and self-renewal activity of neural stem cells through translational repression of m-Numb. However, its translation repression mechanism has remained unclear. Here, we identify poly(A) binding protein (PABP) as an Msi1-binding protein, and find Msi1 competes with eIF4G for PABP binding. This competition inhibits translation initiation of Msi1's target mRNA. Indeed, deletion of the PABP-interacting domain in Msi1 abolishes its function. We demonstrate that Msi1 inhibits the assembly of the 80S, but not the 48S, ribosome complex. Consistent with these conclusions, Msi1 colocalizes with PABP and is recruited into stress granules, which contain the stalled preinitiation complex. However, Msi1 with mutations in two RNA recognition motifs fails to accumulate into stress granules. These results provide insight into the mechanism by which sequence-specific translational repression occurs in stem cells through the control of translation initiation.

Abbreviations used in this paper: CBB, Coomassie brilliant blue; fLuc, firefly luciferase; IMP, insulin-like growth factor 2 mRNA binding protein; IRES, internal ribosomal entry site; MCS, Msi1-binding consensus sequence; MCSmut, mutated MCS; Msi, Musashi; NSC, neural stem cell; NSPC, neural stem/precursor cell; PABP, poly(A) binding protein; PB, processing body; QCM, quartz crystal microbalance; RRL, rabbit reticulocyte lysate; RRM, RNA recognition motif; SG, stress granule; TAP, tandem affinity purification; UTR, untranslated region; VZ, ventricular zone.


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