Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 5, Pages 3362-3371Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1343
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Funding
- Associazione Ricerca Italiana sulla Sclerosi Laterale Amiotrofica (AriSLA) [TARMA]
- Thierry-Latran Fondation [project REHNPALS]
- AriSLA (Associazione Ricerca Italiana sulla Sclerosi Laterale Amiotrofica)
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TDP-43 is a nuclear protein involved in many aspects of RNA metabolism. To ensure cellular viability, its expression levels within cells must be tightly regulated. We have previously demonstrated that TDP-43 autoregulation occurs through the activation of a normally silent intron in its 3'-UTR sequence that results in the use of alternative polyadenylation sites. In this work, we analyse which is the dominant event in autoregulation: the recognition of the splice sites of 3'-UTR intron 7 or the intrinsic quality of the alternative polyadenylation sites. A panel of minigene constructs was tested for autoregulation functionality, protein production and subcellular messenger RNA localization. Our data clearly indicate that constitutive spliceosome complex formation across intron 7 does not lead to high protein production but, on the contrary, to lower TDP-43 messenger RNA and protein levels. This is due to altered nucleocytoplasmic distribution of the RNA that is mostly retained in the nucleus and degraded. This study provides a novel in-depth characterization of how RNA binding proteins can autoregulate their own levels within cells, an essential regulatory process in maintaining cellular viability.
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