Fly versus man: Evolutionary impairment of nucleolar targeting affects the degradome of Drosophila's Taspase1

Désirée Wünsch, Angelina Hahlbrock, Christina Heiselmayer, Sandra Bäcker, Patrick Heun, Dorothee Goesswein, Walter Stöcker, Tanja Schirmeister, Günter Schneider, Oliver H. Krämer, Shirley K. Knauer, Roland H. Stauber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Human Taspase1 is essential for development and cancer by processing critical regulators, such as the mixed-lineage leukemia protein. Likewise, its ortholog, trithorax, is cleaved by Drosophila Taspase1 (dTaspase1), implementing a functional coevolution. To uncover novel mechanism regulating protease function, we performed a functional analysis of dTaspase1 and its comparisontothe human ortholog.dTaspase1contains an essential nucleophile threonine195, catalyzing cis cleavage into its a- and b-subunits. A cell-based assay combined with alanine scanning mutagenesis demonstrated that the target cleavage motif for dTaspase1 (Q3[F/I/L/M]2D1 G1'X2X3'v) differs significantly from the human ortholog (Q3[F,I,L,V]2D1G1'X2'X3'vD4'), predicting an enlarged degradome containing 70 substrates for Drosophila. In contrast to human Taspase1, dTaspase1 shows no discrete localization to the nucleus/nucleolus due to the lack of the importin-a/nucleophosmin1 interaction domain (NoLS) conserved in all vertebrates. Consequently, dTaspase1 interacts with neither the Drosophila nucleoplasmin-like protein nor human nucleophosmin1. The impact of localization on the protease's degradome was confirmed by demonstrating that dTaspase1 did not efficiently process nuclear substrates, such as upstream stimulatoryfactor2.However,geneticintroductionofthe NoLS into dTaspase1 restored its nucleolar localization, nucleophosmin1 interaction, and efficient cleavage of nuclearsubstrates.Wereportthatevolutionaryfunctional divergence separating vertebrates from invertebratescan be achieved for proteases by a transport/localizationregulated mechanism.

Original languageEnglish
Pages (from-to)1973-1985
Number of pages13
JournalThe FASEB Journal
Volume29
Issue number5
DOIs
Publication statusPublished - 1 May 2015

Keywords

  • Cancer
  • Development
  • Leukemia
  • Protease
  • Threonine aspartase

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