Palestrante: Prof. Dr. Igor Cestari - Institute of Parasitology, McGill University
Moderador: Prof. Dr. Nilmar Moretti - Department of Microbiology, Immunology and Parasitology - Unifesp
Trypanosoma brucei evades the host antibody clearance by periodically switching its variant surface glycoprotein (VSGs) coat. T. brucei encodes about 2,500 VSG genes, but only one VSG gene is expressed at a time from one of the 20 telomeric expression sites (ESs). T. brucei switches VSG expression by alternating ES transcription or by VSG gene recombination. We showed that phosphoinositide (PIP) proteins regulate the exclusive expression of VSG genes in T. brucei bloodstream forms (BFs) (1). We showed that a nuclear PIP 5-phosphatase (PIP5Pase) associates with repressor-activator protein 1 (RAP1) within a 0.9 megadalton protein complex, which includes about 20 proteins (2). PIP5Pase dephosphorylates PI(3,4,5)P3 at the 5-phosphate position, and it is essential for VSG silencing (1,2). Here, we show that PIP5Pase regulates VSG developmental silencing, and we discuss a model in which PIP5Pase regulates VSG silencing in BFs. PIP5Pase substrate PI(3,4,5)P3 binds RAP1 via its N-terminal BRCT domain, and controls RAP1 association with ES chromatin, namely 70 bp and telomeric repeats. The loss of PIP5Pase activity likely results in local PI(3,4,5)P3 accumulation. PI(3,4,5)P3 displaces RAP1 from ESs and results in VSG transcription, likely by changing ES chromatin organization.