Characterization of ADAT2/3 molecules in Trypanosoma cruzi and regulation of mucin gene expression by tRNA editing

FLEMIN, IAN ; CARMONA SJ; ZAHN, ASTRID; A BUSCAGLIA, CARLOS; BERTOTTI, SANTIAGO; CENTENO CAMEÁN, CAMILA; BALOUZ, VIRGINIA; ALFONZO JD; CAMARA MM; AGÜERO F; DI NOIA, JAVIER M

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Lugar: Londres; Año: 2022 vol. 479 p. 561 - 580

0264-6021

Adenosine-to-inosine conversion at position 34 (A34-to-I) of certain tRNAs is essential forexpanding their decoding capacity. This reaction is catalyzed by the adenosine deami-nase acting on tRNA (ADAT) complex, which in Eukarya is formed by two subunits:ADAT2 and ADAT3. We herein identified and thoroughly characterized the ADAT mole-cules from the protozoan pathogen Trypanosoma cruzi, the causative agent of ChagasDisease. TcADAT2 and TcADAT3 spontaneously form a catalytically active complex, asshown by expression in engineered bacteria and/or by the increased ex vivo tRNA A-to-Ideamination activity of T. cruzi epimastigotes overexpressing TcADAT subunits.Importantly, enhanced TcADAT2/3 activity in transgenic parasites caused a shift in theirin vivo tRNAThrAGU signature, which correlated with significant changes in the expression ofthe Thr-rich TcSMUG proteins. To our knowledge, this is the first evidence indicating thatT. cruzi tRNA editing can be modulated in vivo, in turn post-transcriptionally changing theexpression of specific genes. Our findings suggest tRNA editing/availability as a forciblestep in controlling gene expression and driving codon adaptation in T. cruzi. Moreover,we unveil certain differences between parasite and mammalian host tRNA editing andprocessing, such as cytosine-to-uridine conversion at position 32 of tRNAThrAGU in T. cruzi, that may be exploited for the identification of novel druggable targets of intervention.