Biology subjects

Etard, C.

Publications and source records attributed to Etard, C..

3 recordsLinked to original sources

bioRxiv2023

Short internal open reading frames regulate the translation of N-terminally truncated proteoforms

Internal translation initiation sites, as revealed by ribosome profiling experiments can potentially drive the translation of many N-terminally truncated proteoforms. We have identified an mRNA cis-regulatory element which regulates their translation. nTRIP6 represents a short nuclear proteoform of the cytoplasmic protein TRIP6. We have previously reported that nTRIP6 regulates the dynamics of skeletal muscle progenitor differentiation. Here we show that nTRIP6 is generated by translation initiation at an internal AUG. Its translation is repressed by an internal short open reading frame (sORF) immediately upstream of the nTRIP6 AUG. Consistent with this representing a more general regulatory feature, we have identified other N-terminally truncated proteoforms which are repressed by internal sORFs. In an in vitro model of myogenic differentiation, the translation of nTRIP6 is transiently de-repressed in a mechanistic Target of Rapamycin Complex 1-dependent manner. Thus, the translation of N-terminally truncated proteoforms can be regulated independently of the canonical ORF.

molecular biology↗

bioRxiv2021

The Bardet-Biedl protein Bbs1 controls photoreceptor outer segment protein and lipid composition

Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a new bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on isolated OSs show that Bbs1 is required for BBSome-entry into OSs and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a new role for Bbs1/BBSome in OS lipid homeostasis and suggest a new pathomechanism underlying retinal degeneration in BBS.

molecular biology↗

bioRxiv2019

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

Whole-genome sequencing was performed on patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome. A unique deep intronic homozygous variant in the PSMC3 gene (c.1127+337A>G, p.Ser376Argfs15*), encoding the 26S proteasome ATPase ring subunit 5 (Rpt5) was identified leading to the transcription of a cryptic exon. Patients fibroblasts exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patients fibroblasts. Upon chemical proteasome inhibition this pathway is however impaired. These cells were unable to compensate for proteotoxic stress although a higher proteasome content. Two different zebrafish studies led to inner ear development anomalies as well as cataracts. PSMC3 proteasome subunit dysfunction leads to various neurological manifestations, early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear, lens and central nervous system development.

genetics↗