Induction of autophagy increases the proteolytic activity of reservosomes during Trypanosoma cruzi metacyclogenesis

LOSINNO, ANTONELLA DENISE; MARTÍNEZ, SANTIAGO JOSÉ; LABRIOLA, CARLOS ALBERTO; CARRILLO, CAROLINA; ROMANO, PATRICIA SILVIA

AUTOPHAGY

LANDES BIOSCIENCE

Año: 2020 p. 1 - 18

1554-8627

AbstractCruzipain, the major cysteine protease of the pathogenic protozoa Trypanosoma cruzi, isan important virulence factor that plays a key role in the parasite nutrition, differentiationand host cell infection. Cruzipain is synthesized as a zymogen, matured, and delivered toreservosomes. These organelles that store proteins and lipids ingested by endocytosisundergo a dramatic decrease in number during the metacyclogenesis of T. cruzi.Autophagy is a process that digests the own cell components to supply energy understarvation or different stress situations. This pathway is important during cell growth,differentiation and death. Previously, we showed that the autophagy pathway of T. cruzi isinduced during metacyclogenesis. This work aimed to evaluate the participation ofmacroautophagy/autophagy in the distribution and function of reservosomes and cruzipainduring this process. We found that parasite starvation promotes the cruzipain delivery toreservosomes. Enhanced autophagy increases acidity and hydrolytic activity in thesecompartments resulting in cruzipain enzymatic activation and self- processing. Inhibition ofautophagy similarly impairs cruzipain traffic and activity than protease inhibitors, whereasmutant parasites that exhibit increased basal autophagy, also display increased cruzipainprocessing under control conditions. Further experiments showed that autophagy inducedcruzipain activation and self-processing promote T. cruzi differentiation and host cellinfection. These findings highlight the key role of T. cruzi autophagy in these processesand reveal a potential new target for Chagas disease therapy.