Conserved functions of human Pelota in <scp>mRNA</scp> quality control of nonstop <scp>mRNA</scp>

Ikeuchi, Ken; Yazaki, Erina; Kudo, Kazuhei; Inada, Toshifumi

doi:10.1002/1873-3468.12366

Cited by 18 publications

(13 citation statements)

References 52 publications

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“…Cells must therefore identify defective rounds of translation and take action before the nascent chain leaves the ribosome (Brandman and Hegde 2016). Degradation of the products of stalled translation is conserved throughout Eukarya (Passos et al 2009;Shao et al 2013Shao et al , 2015Shao and Hegde 2014;Ikeuchi et al 2016), and failures in this response have been linked to dysregulation of protein homeostasis (Choe et al 2016;Defenouillere et al 2016;Yang et al 2016;Yonashiro et al 2016) and neurodegenerative phenotypes (Chu et al 2009;Ishimura et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation

Sitron

Park

Brandman

2017

RNA

127

150

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Premature arrest of protein synthesis within the open reading frame elicits a protective response that degrades the incomplete nascent chain. In this response, arrested 80S ribosomes are split into their large and small subunits, allowing assembly of the ribosome quality control complex (RQC), which targets nascent chains for degradation. How the cell recognizes arrested nascent chains among the vast pool of actively translating polypeptides is poorly understood. We systematically examined translation arrest and modification of nascent chains in Saccharomyces cerevisiae to characterize the steps that couple arrest to RQC targeting. We focused our analysis on two poorly understood 80S ribosome-binding proteins previously implicated in the response to failed translation, Asc1 and Hel2, as well as a new component of the pathway, Slh1, that we identified here. We found that premature arrest at ribosome stalling sequences still occurred robustly in the absence of Asc1, Hel2, and Slh1. However, these three factors were required for the RQC to modify the nascent chain. We propose that Asc1, Hel2, and Slh1 target arresting ribosomes and that this targeting event is a precondition for the RQC to engage the incomplete nascent chain and facilitate its degradation.

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Section: Introductionmentioning

confidence: 99%

Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation

Sitron

Park

Brandman

2017

RNA

127

150

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“…Subsequent studies structurally associated Hbs1 with eRF3 and eEF1A [13], and recognition of Dom34 as an Hbs1-interacting protein functionally linked the complex to translation [14]. Recent biochemical studies have shown that Dom34:Hbs1 promotes the dissociation of the stalled ribosome into subunits [8, 15, 16] during aberrant translation. Subunit dissociation is a critical component of canonical ribosomal recycling, a process to reutilize ribosomes from a terminated or aberrant round of translation.…”

Section: Introductionmentioning

confidence: 99%

Mammalian Hbs1L deficiency causes congenital anomalies and developmental delay associated with Pelota depletion and 80S monosome accumulation

et al. 2019

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Hbs1 has been established as a central component of the cell’s translational quality control pathways in both yeast and prokaryotic models; however, the functional characteristics of its human ortholog (Hbs1L) have not been well-defined. We recently reported a novel human phenotype resulting from a mutation in the critical coding region of the HBS1L gene characterized by facial dysmorphism, severe growth restriction, axial hypotonia, global developmental delay and retinal pigmentary deposits. Here we further characterize downstream effects of the human HBS1L mutation. HBS1L has three transcripts in humans, and RT-PCR demonstrated reduced mRNA levels corresponding with transcripts V1 and V2 whereas V3 expression was unchanged. Western blot analyses revealed Hbs1L protein was absent in the patient cells. Additionally, polysome profiling revealed an abnormal aggregation of 80S monosomes in patient cells under baseline conditions. RNA and ribosomal sequencing demonstrated an increased translation efficiency of ribosomal RNA in Hbs1L-deficient fibroblasts, suggesting that there may be a compensatory increase in ribosome translation to accommodate the increased 80S monosome levels. This enhanced translation was accompanied by upregulation of mTOR and 4-EBP protein expression, suggesting an mTOR-dependent phenomenon. Furthermore, lack of Hbs1L caused depletion of Pelota protein in both patient cells and mouse tissues, while PELO mRNA levels were unaffected. Inhibition of proteasomal function partially restored Pelota expression in human Hbs1L-deficient cells. We also describe a mouse model harboring a knockdown mutation in the murine Hbs1l gene that shared several of the phenotypic elements observed in the Hbs1L-deficient human including facial dysmorphism, growth restriction and retinal deposits. The Hbs1l KO mice similarly demonstrate diminished Pelota levels that were rescued by proteasome inhibition.

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“…X420Y mutation in MITF introduces 99 nucleotide acids before the alternative in-frame stop codon; it is likely to trigger nonstop mRNA decay. 32, 33 …”

Section: Discussionmentioning

confidence: 99%

Functional analysis of a nonstop mutation in MITF gene identified in a patient with Waardenburg syndrome type 2

et al. 2017

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Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associated transcription factor (MITF) gene gives rise to WS2. Here, we identified a novel WS-associated mutation at the stop codon of MITF (p.X420Y) in a Chinese WS2 patient. This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively. The mutation led to a reduction in the transcriptional activities, whereas the DNA-binding activity was not altered. We show that the foremost mechanism was haploinsufficiency for the mild phenotypes of WS2 induced in X420Y MITF.

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Conserved functions of human Pelota in mRNA quality control of nonstop mRNA

Cited by 18 publications

References 52 publications

Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation

Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation

Mammalian Hbs1L deficiency causes congenital anomalies and developmental delay associated with Pelota depletion and 80S monosome accumulation

Functional analysis of a nonstop mutation in MITF gene identified in a patient with Waardenburg syndrome type 2

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