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J. Biol. Chem., Vol. 280, Issue 45, 37572-37584, November 11, 2005

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TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail

AN IMPORTANT REGION FOR THE INHIBITION OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR EXON 9 SPLICING^*

From the International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy

TDP-43 is a highly conserved nuclear factor of yet unknown function that binds to ug-repeated sequences and is responsible for cystic fibrosis transmembrane conductance regulator exon 9 splicing inhibition. We have analyzed TDP-43 interactions with other splicing factors and identified the critical regions for the protein/protein recognition events that determine this biological function. We show here that the C-terminal region of TDP-43 is capable of binding directly to several proteins of the heterogeneous nuclear ribonucleoprotein (hnRNP) family with well known splicing inhibitory activity, in particular, hnRNP A2/B1 and hnRNP A1. Mutational analysis showed that TDP-43 proteins lacking the C-terminal region could not inhibit splicing probably because they were unable to form the hnRNP-rich complex involved in splicing inhibition. Finally, through splicing complex analysis, we show that splicing inhibition mediated by TDP-43 occurs at the earliest stages of spliceosomal assembly.

Received for publication, May 20, 2005 , and in revised form, September 7, 2005.

^* This work was supported by Grant GGP02453 from the Telethon Onlus Foundation (Italy) and Grant RBNE01W9PM from Fondo per Gli Investimenti della Recerca di Base. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy. Tel.: 39-040-375-7337; Fax: 39-040-375-7361; E-mail: baralle{at}icgeb.org.

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