Trypanosoma cruzi High Mobility Group B (TcHMGB) can alter chromatin structure

ALONSO, VICTORIA LUCÍA; CRIBB, PAMELA; PERDOMO, VIRGINIA; TAVERNELLI, LUIS EMILIO; SERRA, ESTEBAN

ON LINE FORMAT

Congreso; XXXI ANNUAL MOLECULAR PARASITOLOGY MEETING; 2020

GENETICS SOCIETY OF AMERICA

High Mobility Group B (HMGB) proteins are conserved nuclear architectural factors involved in chromatin remodeling and important nuclear events like DNA transcription, replication, recombination and repair. Some HMGBs also play key roles outside the cell, acting as ?alarmins? or Damage Associated Molecular Patterns (DAMPs) and are involved in the pathogenesis of many autoimmune, infectious and inflammatory chronic diseases.TcHMGB, the HMGB from Trypanosoma cruzi, has two "HMG box" DNA-binding domains and a specific amino-terminal region unique of trypanosomatid HMGBs. This N-term sequence bears a nuclear localization signal (NLS) and a "DEK-C terminal" domain, which may confer special DNA-binding characteristics to the protein. Both the funvolved in ll length TcHMGB and its separated domains showed architectural features like the ability to bend linear DNA and bind to non-canonical structures like cruciform DNA in vitro. Also, TcHMGB can affect DNA structure in vivo, where its overexpression resulted in an altered chromatin state. Overexpression of TcHMGB also caused a dramatic decrease in epimastigotes growth possibly as a consequence of a delayed cell cycle progression with accumulation of parasites in G2/M phase and impaired cytokinesis. Amastigotes´ replication was also reduced in an in vitro infection model, as was the trypomastigotes´ infection efficiency and the number of finally released trypomastigotes. We propose that chromatin changes associated to the increased TcHMGB nuclear content, may affect parasite functions in sum resulting in a reduced fitness.Finally, we also demonstrated that TcHMGB, like human HMGB1, can be secreted out of the cell and induce the production of inflammatory mediators both in vitro and in vivo.Taken together, our results suggest that the TcHMGB protein can be considered a pleiotropic player involved not only in trypanosome key cellular processes, but also it should be considered a putative actor in Chagas disease pathogenesis.