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C18orf21/RMP24 and Nepro/RMP64 are RNase MRP-specific subunits required for 40S ribosome biogenesis

ABSTRACT: RNase MRP and RNase P are evolutionarily related complexes that facilitate rRNA and tRNA biogenesis, respectively. The two enzymes share nearly all protein subunits and have evolutionarily related catalytic RNAs. Notably, RNase P includes a unique subunit, RPP21, whereas no RNase MRP-specific proteins have been found in humans, limiting molecular analyses of RNase MRP function. Here, we identify the RNase MRP-specific proteins, C18orf21/RMP24 and NEPRO/RMP64. C18orf21/RMP24 and RPP21 display significant structural homology, but we identify specific regions that drive interactions with their respective complexes. By targeting these RNase MRP-specific subunits, our functional analysis reveals that RNase MRP is essential rRNA processing and preferentially required for 40S ribosome biogenesis. Finally, we determine that disease-associated mutations in RMP64 impair its association with RNase MRP subunits. Together, our findings elucidate the molecular determinants of RNase MRP function and underscore its critical role in ribosome biogenesis and disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Cervix Epithelium

SUBMITTER: Eric Smith

LAB HEAD: Iain Cheeseman

PROVIDER: PXD065571 | Pride | 2025-10-23

REPOSITORIES: Pride

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			Action	DRS
	20240906_Exploris_ES902_CheesemanLab_ES_Sample_259E.mzML	Mzml
	20240906_Exploris_ES902_CheesemanLab_ES_Sample_259E.mzid	Mzid
	20240906_Exploris_ES902_CheesemanLab_ES_Sample_259E.raw	Raw
	20240906_Exploris_ES902_CheesemanLab_ES_Sample_476E.raw	Raw
	20240906_Exploris_ES902_CheesemanLab_ES_Sample_477E.raw	Raw

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Project description:The pathogenicity of the malaria parasites results from their ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC)(Boddey and Cowman, 2013; Cowman et al., 2017; Tan and Blackman, 2021), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-MRP; Master Regulator of Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post-invasion (h.p.i.). When expression of PfAP2-MRP at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-MRP parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes thought to be involved in these key life cycle processes. Disruption of PfAP2-MRP expression at 16 h.p.i. results in transcriptional activation of the majority of silenced var genes observed at both bulk and single-cell level. This is also reflected by a significantly higher level of immuno-recognition of the exported proteins on the ∆PfAP2-MRP parasite-infected RBCs by pooled sera from malaria-exposed individuals from an endemic region. In addition, overexpression of many early gametocyte marker genes was also observed in ∆PfAP2-MRP parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-MRP directly regulates these genes by binding to their promoter region or indirectly through 14 other downstream AP2 transcription factors. Taken together, we conclude that PfAP2-MRP is an upstream transcriptional regulator that participates in mutually exclusive expression patterns shown by the var family of genes and is a critical determinant of parasite's growth during the IDC.

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C18orf21/RMP24 and Nepro/RMP64 are RNase MRP-specific subunits required for 40S ribosome biogenesis

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