Authors
Joaquín Costa, Yoanna Herrera-Preval, Gervasio Puca, Alejandro D Nusblat, Antonio D Uttaro
Published in
The FEBS journal. Jun 29, 2026. Epub Jun 29, 2026.
Abstract
The free-living ciliate Tetrahymena thermophila avidly acquires exogenous sterols through phagocytosis and pinocytosis. We have previously shown that the aminosteroid U18666A, known to bind the mammalian Niemann-Pick C1 protein (NPC1), completely inhibited both uptake processes, resulting in cholesterol accumulation in phagosome-like vesicles and severe inhibition of sterol esterification. This suggests a blockage of sterol transfer between phagolysosomes and the endoplasmic reticulum (ER). The ciliate possesses a 50% similar ortholog of NPC1 (NPC, TTHERM_00672270), previously localized to the phagosomes. Since U18666A binds to other cholesterol-related proteins, an off-target effect in T. thermophila could not be ruled out. Therefore, we analyzed the role of Tt-NPC in cholesterol transfer using reverse genetics. Tt-NPC lacks the equivalent N-terminal domain of NPC1 (NTD). Using NTD as a query, a protein with 38% similarity (TTHERM_00336030) was retrieved and subsequently named NTD. Knockdown of either the Tt-NPC or Tt-NTD genes produced similar phenotypes. The cell growth was arrested after cholesterol supplementation, with cholesterol accumulating in phagosome-like vesicles. Additionally, the ER processes, sterol esterification and bioconversion, were severely impaired. Transcriptional regulation of two well-characterized sterol-responsive genes was lost in Tt-NTD and significantly delayed in Tt-NPC. This evidence suggests the presence of a functional ortholog of NPC1 in T. thermophila, composed of two peptides and a partial conservation of sterol trafficking across eukaryotic lineages.
PMID:
42366915
Bibliographic data and abstract were imported from PubMed on 29 Jun 2026.
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