Asymmetric protein sorting via localized translation - The role of ZBP proteins in directing mRNA localization and translation

Dr. Stefan Hüttelmaier

Project Summary:

Active transport of translationally silenced mRNAs is a conserved mechanism to accomplish asymmetric protein sorting via spatially restricted protein synthesis. In developing, but also mature neurons this process of restricting translation of specific transcripts to defined subcellular locations is essential for growth cone guidance and the modulation of synaptic plasticity. However, the molecular mechanisms directing asymmetric sorting of mRNAs and their translational activation upon delivery are only poorly understood.
In recent studies, we revealed that the RNA-binding protein ZBP1 (Zipcode binding protein) directs spatially restricted -actin protein synthesis to growth cones and dendrites of primary neurons. Presumably, transport of the -actin mRNA requires an inhibition of translation that is facilitated by ZBP1. In the cell periphery ZBP1 becomes phosphorylated by Src-kinase leading to a release of the protein from associated mRNA and subsequent synthesis of -actin protein. Although this process was identified to be essential for growth cone guidance and neurite outgrowth, the composition and functional interplay of protein factors associated with ZBP1 in cytoplasmic mRNPs remains elusive.
 Therefore, we aim at characterizing the composition and functional interplay of ZBP1 associated factors in cytoplasmic mRNPs, termed locasomes that modulate mRNA transport in neurons and localized -actin translation at growth cones. Moreover, we intend to characterize if and how signaling events besides Src-mediated phosphorylation guide the localized translation of -actin mRNA by controlling ZBP1 function.

Selected publications (2007-09):

1.    Keil R, Wolf A, Huttelmaier S, Hatzfeld M. Beyond Regulation of Cell Adhesion: Local Control of RhoA at the Cleavage Furrow by the p0071 Catenin. Cell Cycle, 2007 Jan 15;6(2):122-7.

2.    Köbel M, Weidensdorfer D, Reinke C, Lederer M, Schmitt WD, Thomssen C, Hauptmann S, Hüttelmaier S. Expression of the RNA-binding Protein IMP1 correlates with poor prognosis in ovarian carcinomas. Oncogene. 2007 Nov 29;26(54):7584-9.

3.    Pan F, Huttelmaier S, Singer RH, Gu W. ZBP2 facilitates binding of ZBP1 to beta-actin mRNA during transcription. Mol Cell Biol. 2007 Dec;27(23):8340-51.

4.    White R, Gonsior C, Krämer-Albers E, Stöhr N, Hüttelmaier S and Trotter J. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNPA2-dependent RNA granules. J Cell Biol. 2008 May 19;181(4):579-86.

5.    Weidensdorfer D., Stöhr N., Baude A, Lederer M, Köhn M, Schierhorn A, Buchmeier S, Wahle E, Hüttelmaier S. Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA. 2009 Jan;15(1):104-15.

6.    Weinlich S, Hüttelmaier S, Schierhorn A, Behrens SE, Ostareck-Lederer A, Ostareck DH. IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3’-UTR. RNA. 2009 Aug: 15(8):1528-42