The RNA-binding protein La is found in most eukaryotes, and despite being essential in many organisms, its function is not completely clear. Trypanosoma brucei, the causative agent of human African trypanosomiasis, encodes a 'classical' La protein (TbLa) composed of a La-motif, two RNA recognition motifs (RRM1 and RRM2α), a C-terminal short basic motif (SBM), and a nuclear localization signal (NLS). In T. brucei, like in most eukaryotes, position 34 of tRNATyr, -Asp, -Asn and -His is modified with queuosine (Q34). The steady-state levels of queuosine-modified tRNA in the insect form (procyclic) of T. brucei can fluctuate dynamically depending on growth conditions, but the mechanism(s) controlling Q34 levels are not well understood. A well-established function of La is in precursor-tRNA 3'-end metabolism, but in this work, we demonstrate that La also controls Q34-tRNA levels. Individual domain deletions showed that while deletion of La motif or RRM1 causes dysregulation of Q34-tRNA levels, no other domain plays a similar role. We also show that La is important for the normal balance of several additional tRNA modifications. These findings are discussed in the context of substrate competition between La and modification enzymes, also highlighting subcellular localization as a key determinant of tRNA function.

Department of Biomolecular Engineering University of California Santa Cruz CA 95064 United States

Department of Molecular Biology Cell Biology and Biochemistry and the Brown RNA Center 225 Dyer Street Brown University Providence R I 02903 United States

Faculty of Science University of South Bohemia České Budějovice 31 370 05 Czech Republic

Institute of Parasitology Biology Centre Czech Academy of Sciences České Budějovice 31 370 05 Czech Republic

New England Biolabs Inc 240 County Road Ipswich Massachusetts 01938 United States

Section on Molecular and Cell Biology Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda MD 20892 United States

The Center for RNA Biology The Ohio State University Columbus Ohio 43210 United States

The Ohio State Biochemistry Program The Ohio State University Columbus Ohio 43210 United States

Thermo Fisher Scientific Lexington MA 04241 United States

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