TheGiardia lambliaribosome structure reveals divergence in translation and quality control pathways

Abstract

Giardia lamblia is a human pathogen of worldwide importance with limited treatment options. Its unusual molecular biology presents targets for new therapies and the opportunity to explore the fundamental features of important biological mechanisms. We determined the structure of the G. lamblia 80S ribosome by cryoelectron microscopy, revealing how it combines eukaryotic and bacterial features. The structure reveals regions that are rapidly evolving, including depletion of A and U bases from its rRNA. Specific features of the G. lamblia ribosome suggest it is less prone to stall on problematic peptide sequences, and that the organism uses altered ribosome quality control pathways compared to other eukaryotes. Examination of translation initiation factor binding sites suggests these interactions are conserved despite a divergent initiation mechanism. This work defines key new questions regarding ribosome-centric biological pathways in G. lamblia and motivates new experiments to explore potential targetable mechanisms.

Cryo-EM structure of the ancient eukaryotic ribosome from the human parasite Giardia lamblia

“…Saccharomyces cerevisiae ) ( Supplementary Figure S7 ). While working on the current manuscript, an additional structural study of the GL ribosome, at lower resolution, was published by Eiler et al in bioRxiv, which discussed a lower amount of adenines and uridines compared to other species and concluded that all the important eIF3 binding sites are conserved ( 48 ).…”

Precise gene models using long-read sequencing reveal a unique poly(A) signal in Giardia lamblia

“…Here, we empirically annotated the 3′ UTRs, for 2630 expressed genes in G. lamblia using a combination of 3′-end short- and long-read sequencing. According to our RNA-seq data ( Eiler et al 2020 ), 6616 of the 9700 predicted coding genes in the genome annotation used for this study are expressed at an FPKM of 10 or higher. This indicates that we have annotated about 40% of the expressed transcriptome.…”

“…Second, consistent with short UTR regions, the genome of G. lamblia is generally very compact such that only eight genes contain introns and five undergo transsplicing, while the number of protein-coding genes is between 5000 to 9000, depending on genome annotation (Xu, Jex, et al, 2020). Third, G. lamblia has streamlined machinery for transcription (Best, 2004;Morrison et al, 2007), splicing (Iyer et al, 2019;Nixon et al, 2002), and translation (Eiler et al, 2020;L. Li & Wang, 2004), and lacks many protein components that are essential for viability in most other eukaryotes, such as the translation initiation factor eIF4G (L. Li & Wang, 2004;Morrison et al, 2007).…”

“…Second, consistent with short UTR regions, the genome of G. lamblia is generally very compact such that only eight genes contain introns and five undergo trans-splicing, while the number of protein-coding genes is between 5000 to 9000, depending on genome annotation ( Xu et al 2020a ). Third, G. lamblia has streamlined machinery for transcription ( Best 2004 ; Morrison et al 2007 ), splicing ( Nixon et al 2002 ; Iyer et al 2019 ), and translation ( Li and Wang 2004 ; Eiler et al 2020 ), and lacks many protein components that are essential for viability in most other eukaryotes, such as the translation initiation factor eIF4G ( Li and Wang 2004 ; Morrison et al 2007 ). Finally, G. lamblia exists in two forms, a dormant and hardy cyst and an infectious trophozoite, making it a potential model system to investigate how cell state and developmental transitions affect gene expression.…”

Precise gene models using long-read sequencing reveal a unique poly(A) signal inGiardia lamblia

“…Second, consistent with short UTR regions, the genome of G. lamblia is generally very compact with only eight genes that contain introns and five that undergo trans-splicing, while the number of protein-coding genes is between 5000 to 9000, depending on genome annotation (Xu, Jex, et al, 2020). Third, G. lamblia has streamlined machinery for transcription (Best, 2004;Morrison et al, 2007), splicing (Iyer et al, 2019;Nixon et al, 2002), and translation (Eiler et al, 2020;L. Li & Wang, 2004), and lacks many protein components that are essential for viability in most other eukaryotes, such as the translation initiation factor eIF4G (L. Li & Wang, 2004).…”