Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay

Zhu, Xiaoqiang; Zhang, He; Mendell, Joshua T.

doi:10.1016/j.celrep.2020.107895

Cited by 43 publications

(49 citation statements)

References 102 publications

(158 reference statements)

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“…After 60S dissociation, a complex including eIF2D/Tma64 (the homolog of eIF2D in yeast), MCST1/Tma20, and DENR/Tma22 is required for 40S ribosome recycling in yeast, and mutation of this complex leads to reinitiation at 3´UTRs [131][132][133] . In general, translation termination is a highly controlled process, with the binding of 80S ribosomes to 3´UTRs only being demonstrated in either terminally differentiated erythrocytes or in the context of mutated translational machinery [79][80][81][82][83][84]134 . In our study, the regulation of ribosome recycling occurs during meiosis prophase in cells that are not terminally differentiated, as spermatocytes will undergo two more rounds of cell division, weeks of further differentiation, and continued protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs

Sun

Wang

et al. 2021

Preprint

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PIWI-interacting small RNAs (piRNAs) protect the germline genome and are essential for fertility. Previously, we showed that ribosomes guide the biogenesis of piRNAs from long non-coding RNAs (lncRNAs) after translating the short open reading frames (ORFs) near their 5′ cap. It remained unclear, however, how ribosomes proceed downstream of ORFs and how piRNA precursors distinguish from other RNAs. It is thus important to test whether a short ORF length is required for substrate recognition for ribosome guided-piRNA biogenesis. Here, we characterized a poorly understood class of piRNAs that originate from the 3′ untranslated regions (3′UTRs) of protein coding genes in mice and chickens. We demonstrate that their precursors are full-length mRNAs and that post-termination 80S ribosomes guide piRNA production on 3′UTRs after translation of upstream long ORFs. Similar to non-sense mediated decay (NMD), piRNA biogenesis degrades mRNA right after pioneer rounds of translation and fine-tunes protein production from mRNAs. Interestingly, however, we found that NMD, along with other surveillance pathways for ribosome recycling are temporally sequestered during the pachytene stage to allow for robust piRNA production. Although 3′UTR piRNA precursor mRNAs code for distinct proteins in mice and chickens, they all harbor embedded transposable elements (TEs) and produce piRNAs that cleave TEs, suggesting that TE suppression, rather than the function of proteins, is the primary evolutionary force maintaining a subset of mRNAs as piRNA precursors. Altogether, we discover a function of the piRNA pathway in fine-tuning protein production and reveal a conserved, general piRNA biogenesis mechanism that recognizes translating RNAs regardless of their ORF length in amniotes.

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Section: Discussionmentioning

confidence: 99%

Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs

Sun

Wang

et al. 2021

Preprint

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“…RNA decay may also be promoted by the CCR4‒NOT deadenylase complex recruited by the SMG5‒SMG7 dimer. Additional NMD factors have recently been identified from NMD reporter-based genome-wide loss-of-function screens ( Alexandrov et al, 2017 ; Zhu et al, 2020 ), although their exact functions in NMD are not fully understood.…”

Section: Mechanisms Of Translation-dependent Mrna Surveillancementioning

confidence: 99%

Regulation of nonsense-mediated mRNA decay in neural development and disease

Lee

Yang

Sun

et al. 2021

Journal of Molecular Cell Biology

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Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon (PTC), but also as a post-transcriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD, as well as an emerging role of NMD dysregulation in neurodegenerative diseases.

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“…Yeast ribosome profiling assays also demonstrated the role that Dom34 plays in recycling ribosomes that escape stop codon and enter downstream non-coding regions [ 135 , 136 ]. In this sense, defects in ISC delivery to ABCE1 due to oxidative stress or lysosomal dysfunction cause stop codon readthrough and ribosome movement into 3′UTRs [ 137 ]. Thus, both ABCE1/Rli1 and Dom34/Pelota are necessary for the access of post-transcriptional regulatory RNA-binding proteins to the 3′UTR of mRNAs since the movement of a single ribosome through the 3′UTR in ABCE1-defective cells is sufficient to displace mRNA-bound proteins [ 137 ].…”

Section: Iron Is Required For Translation Terminationmentioning

confidence: 99%

“…In this sense, defects in ISC delivery to ABCE1 due to oxidative stress or lysosomal dysfunction cause stop codon readthrough and ribosome movement into 3′UTRs [ 137 ]. Thus, both ABCE1/Rli1 and Dom34/Pelota are necessary for the access of post-transcriptional regulatory RNA-binding proteins to the 3′UTR of mRNAs since the movement of a single ribosome through the 3′UTR in ABCE1-defective cells is sufficient to displace mRNA-bound proteins [ 137 ]. Recent data have demonstrated that non-sense mediated decay and post-transcriptional regulatory pathways such as microRNA and ARE-mediated decay are impaired upon depletion of ABCE1 [ 137 ].…”

Section: Iron Is Required For Translation Terminationmentioning

confidence: 99%

Iron in Translation: From the Beginning to the End

2021

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Iron is an essential element for all eukaryotes, since it acts as a cofactor for many enzymes involved in basic cellular functions, including translation. While the mammalian iron-regulatory protein/iron-responsive element (IRP/IRE) system arose as one of the first examples of translational regulation in higher eukaryotes, little is known about the contribution of iron itself to the different stages of eukaryotic translation. In the yeast Saccharomyces cerevisiae, iron deficiency provokes a global impairment of translation at the initiation step, which is mediated by the Gcn2-eIF2α pathway, while the post-transcriptional regulator Cth2 specifically represses the translation of a subgroup of iron-related transcripts. In addition, several steps of the translation process depend on iron-containing enzymes, including particular modifications of translation elongation factors and transfer RNAs (tRNAs), and translation termination by the ATP-binding cassette family member Rli1 (ABCE1 in humans) and the prolyl hydroxylase Tpa1. The influence of these modifications and their correlation with codon bias in the dynamic control of protein biosynthesis, mainly in response to stress, is emerging as an interesting focus of research. Taking S. cerevisiae as a model, we hereby discuss the relevance of iron in the control of global and specific translation steps.

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Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay

Cited by 43 publications

References 102 publications

Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs

Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs

Regulation of nonsense-mediated mRNA decay in neural development and disease

Iron in Translation: From the Beginning to the End

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