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Functional and protein interaction analysis of Nop7 in trypanosomatid parasites

ABSTRACT: Nucleolar protein 7 (Nop7), also known as PES1 or Pescadillo, is a conserved factor essential for ribosome biogenesis, cell cycle progression, proliferation, and nucleolar organization in yeast and metazoans. Its dysregulation has been linked to several non-infectious human diseases. In this study, we characterized Nop7 in the trypanosomatids parasites Trypanosoma brucei and Leishmania major, microorganisms distinguished by their atypical ribosomes whose 28S-type ribosomal RNA is multifragmented. In silico analyses indicates that trypanosomatids Nop7 contains putative structural adaptations that could be necessary for its specialized function, working as scaffold for additional protein-protein interactions. PTP-tagged version of Nop7 localize to the nucleolus throughout cell cycle in both species. To define the Nop7 interactome, we performed tandem affinity purifications followed by mass spectrometry. This proteomic approach revealed extensive association of TbNop7 and LmNop7 with numerous transient trans-acting factors, including Erb1 and Ytm1, which together with Nop7 form a heterotrimeric subcomplex (known as the PeBow complex in mammals) required for the 60S ribosome subunit maturation in other eukaryotes. We also identified several hypothetical nucleolar proteins, representing potential novel components of the trypanosomatid ribosome biogenesis machinery. Comparative proteomic features between trypanosomatids and human underscoring parasite-specific factors potentially needed for ribosome production pathways. RNAi-mediated depletion of Nop7 in T. brucei significantly impaired proliferation, induced pronounced morphological abnormalities, and altered DNA content, highlighting its critical role in cell cycle progression and survival. Collectively, our findings provide the first proteomic characterization of Nop7-associated factors in T. brucei and L. major in culture, revealing new candidates for functional investigation and potential therapeutic targeting.

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ORGANISM(S): Trypanosoma Brucei Leishmania Major Strain Friedlin

SUBMITTER: Ebbing de Jong

LAB HEAD: Tomás Nepomuceno Mejía

PROVIDER: PXD071778 | Pride | 2026-05-14

REPOSITORIES: Pride

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Project description:The nucleolus is a dynamic structure where ribosome subunits are produced. Indeed, nucleoli respond to any change in cellular homeostasis by altering the rate of ribosome biogenesis, thus working as a stress sensor. Consequently, imbalances in ribosome biogenesis promotes changes in morphology and function and can evoke a nucleolar stress and DNA damage responses. These changes in nucleolar architecture and composition, culminating in impaired ribosome biogenesis, prompt the emergence of the nucleolar stress, which manifests as a contributing factor in aging and cancer. Here, we illuminate the pivotal role that the RNA binding protein Hnrnpk plays in orchestrating nucleolar dynamics and sustaining ribosome function. As a ribonucleoprotein, Hnrnpk governs the chaperoning of nascent transcripts to facilitate their processing and subsequent nuclear export for ribosomal integration. When overexpressed, Hnrnpk induces disruptive alterations in nucleolar structure, resulting in stress-like phenotypes; such as unbalances of molecular components, accumulation and delocalization of nucleolin, and decrease expression and occupation of fibrillarin. Consequentially, these aberrations in nucleolar equilibrium engenders a disruption in ribosome biogenesis and concomitantly halts the protein translation machinery. Nucleolin (Ncl) haploinsufficiency is correlated with enlarged nucleoli, increased ribosome components, heightened translational rates translation and a concomitant decrease in lifespan. Thus, an Hnrnpk overexpression-dependent surge of Ncl levels stemming may instigate a decline in nucleolar integrity and perturbations in ribosome biogenesis—an event intimately associated with ribosomopathies and the ensuing syndrome of bone marrow failure syndrome. Intersting, the aging process shares a number of common biological hallmarks with bone marrow failure. Again, alterations in Hnrnpk expression, specifically overexpression triggers nucleolar stress, driving cell cycle arrest and senescence of the cells. Our investigations demonstrate that p53, c-Myc and Ncl haploinsufficiency rescue these Hnrnpk-mediated phenotypes. Collectively, the data begin to decipher novel signaling pathway involved in nucleolar stress - ribosome stress – and p53 driven cell cycle arrest that governs this process. Together, these findings support the idea that nucleolar disturbances contribute to ribosome impairment, thus catalyzing the genesis of hematopoietic anomalies and aging process. Significantly, this study elucidates Hnrnpk as a previously unrecognized master regulator within these intricate ribosomal mechanisms; providing a novel window to view the orchestration of nucleolar integrity, ribosome function, and cellular senescence.

			Action	DRS
	20220711_Santiago_3.mgf	Mgf
	20220711_Santiago_3.mzML	Mzml
	20220711_Santiago_3.mzid	Mzid
	20220711_Santiago_3.raw	Raw
	20220711_Santiago_4.mgf	Mgf

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Functional and protein interaction analysis of Nop7 in trypanosomatid parasites

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