How are circRNAs translated by non-canonical initiation mechanisms?

Diallo, Leila; Tatin, Florence; David, Florian; Godet, Anne-Claire; Zamora, Audrey; Prats, Anne-Catherine; Garmy‐Susini, Barbara; Lacazette, Éric

doi:10.1016/j.biochi.2019.06.015

Cited by 64 publications

(55 citation statements)

References 76 publications

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“…It is likely that all human individuals generate circAβ-a RNA, indicating a possible role in the pathogenesis of sporadic AD. It has already been demonstrated that translation of some circRNA could be activated under certain stress conditions [ 58 , 69 , 70 ]. Further analysis is required to investigate whether circAβ-a level and its translation is elevated in the aging brain (especially in AD pathology), which could be triggered by endogenous or environmental conditions eliciting various cellular stresses, such as oxidative damage [ 71 , 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

Raabe

et al. 2020

Cells

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Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides—a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates.

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Section: Discussionmentioning

confidence: 99%

Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

Raabe

et al. 2020

Cells

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“…IRESs, elements located in the leader region of a restricted class of mRNA, allow the initiation of mRNA translation independently on the Cap-structure [25,36,37]. The alternative mechanism of translation mediated by IRESs is important when the attenuation of global protein synthesis occurs in cells undergoing stress conditions, such as ER stress, hypoxia, UV irradiation, etc.…”

Section: Discussionmentioning

confidence: 99%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5 untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed. Int. J. Mol. Sci. 2020, 21, 1206 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B). Int. J. Mol. Sci. 2020, 21, 1206 Then ACLY levels showed a constant increase, becoming about 3.5-fold greater than the control after 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B).

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“…Ce dernier point est particulièrement intéressant car il suggère que les circARN, ou au moins certains d'entre eux, pourraient être traduits en conditions de stress. Alors que les circARN identifiés présentent généralement des IRES en 5' du codon initiateur, l'ARN circulaire circSHPRH, produit par le gène codant l'hélicase SHPRH (SNF2 histone-linker PHD RING helicase), possède un IRES qui est situé en 3' du codon initiateur et qui permet l'expression d'une protéine de 146 kDa [21,22]. Cette particularité du circSHPRH provient de ce que la totalité de sa séquence est codante.…”

Section: Les Circarn Une Nouvelle Classe D'arn Messagersunclassified

L’ARN circulaire nous joue-t-il des tours ?

et al. 2020

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L’ARN n’a pas dit son dernier mot… avec l’émergence des ARN circulaires (circARN). Quatorze pour cent des gènes humains produisent en effet des circARN par un mécanisme d’épissage alternatif : le rétro-épissage. Chez l’homme, plus de 100 000 circARN différents ont ainsi été répertoriés. Dans le noyau, ils régulent la transcription ou l’épissage des ARNm, alors que, dans le cytoplasme, ils séquestrent des miARN et des protéines, ou sont traduits par un mécanisme d’initiation interne de la traduction. Ces circARN constituent en fait un outil biotechnologique performant car leur traduction est très stable dans le temps, et les circARN exogènes induisent moins de réponses immunitaires que les ARNm linéaires. Dans cette revue, nous discuterons, après les avoir décrits, du rôle des circARN dans différents processus pathologiques et de leur utilisation en biotechnologie.

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How are circRNAs translated by non-canonical initiation mechanisms?

Cited by 64 publications

References 76 publications

Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

L’ARN circulaire nous joue-t-il des tours ?

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