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APC couples neuronal mRNAs to multiple kinesins, EB1 and shrinking microtubule ends for bidirectional mRNA motility

Authors :
Sebastian J. Baumann
Julia Grawenhoff
Elsa C. Rodrigues
Silvia Speroni
Maria Gili
Artem Komissarov
Sebastian P. Maurer
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

Understanding where in the cytoplasm mRNAs are translated is increasingly recognized as being as important as knowing the timing and level of protein expression. mRNAs are localized via active motor-driven transport along microtubules (MTs) but the underlying essential factors and dynamic interactions are largely unknown. Using biochemical in vitro reconstitutions with purified mammalian proteins, multicolor TIRF-microscopy, and interaction kinetics measurements, we show that adenomatous polyposis coli (APC) enables kinesin-1- and kinesin-2-based mRNA transport, and that APC is an ideal adaptor for long-range mRNA transport as it forms highly stable complexes with 3'UTR fragments of several neuronal mRNAs (APC-RNPs). The kinesin-1 KIF5A binds and transports several neuronal mRNP components such as FMRP, PURα and mRNA fragments weakly, whereas the transport frequency of the mRNA fragments is significantly increased by APC. APC-RNP-motor complexes can assemble on MTs, generating highly processive mRNA transport events. We further find that end-binding protein 1 (EB1) recruits APC-RNPs to dynamically growing MT ends and APC-RNPs track shrinking MTs, producing MT minus-end-directed RNA motility due to the high dwell times of APC on MTs. Our findings establish APC as a versatile mRNA-kinesin adaptor and a key factor for the assembly and bidirectional movement of neuronal transport mRNPs. This work was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) [BFU2017-85361-P], [PID2020-114870GB-I00], [BFU2015-62550-ERC], the Ministerio de Ciencia, Innovación y Universidades and Fondo Social Europeo (FSE) [PRE2018-084501], Juan de la Cierva-Incorporación Program [IJCI-2015-25994], the Human Frontiers in Science Program (HFSP) [RGY0083/2016], and the European Research Council (ERC) [H2020-MSCA-IF-2014-659271.]. We further acknowledge the support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa’ [SEV-2012-0208].

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....34ff25c43e9558895b93a3547e9ded1d
Full Text :
https://doi.org/10.1101/2022.07.01.498380