Biology subjects

Arnoult, D.

Publications and source records attributed to Arnoult, D..

3 recordsLinked to original sources

bioRxiv2026

Gene identity, not variant effect, dominates ClinVar benchmarks of missense pathogenicity predictors

Missense pathogenicity predictors are routinely benchmarked against ClinVar, whose labels are strongly structured by gene: genes under diagnostic scrutiny accumulate pathogenic submissions while incidentally sequenced genes accumulate benign ones. We asked how much of a benchmark score this structure alone can produce. On 197,904 ClinVar missense variants validated against UniProt canonical sequences, a null model using no variant-level information, scoring each variant only by the pathogenic fraction of its own gene, reaches an area under the receiver operating characteristic curve (AUROC) of 0.921 under a random 10-fold split. On a common intersection of 169,989 variants, four current predictors exceed it by only 0.036 to 0.044. The inflation is not uniform, so it does not cancel when predictors are compared: under within-gene evaluation the ranking inverts, AlphaMissense rising from third to first and gMVP falling to third (p < 0.0001). The inversion survives removal of ceiling genes and replicates on an independently curated benchmark. Because both rankings derive from the same ClinVar labels, we arbitrated between them using data with no gene-level structure: agreement with 47 human deep mutational scanning assays matches the within-gene ranking and inverts the conventional one (p = 0.027, 0.0023). Across twenty-two dbNSFP predictors scored on one common intersection of 112,248 variants, with each tool's exposure to clinical labels registered before any score was extracted, predictors never trained on such labels sit 0.051 AUROC behind supervised ones globally but only 0.026 behind within genes (difference +0.025 [+0.023, +0.027], p < 0.0001). Leave-one-out correction, the standard remedy, is worth 0.002 AUROC. Much of ClinVar benchmark performance reflects gene identity rather than variant effect, and the distortion changes which predictor a benchmark ranks first, in a direction experimental data contradicts. We release genenull, a single-file implementation, so reporting this baseline costs one function call.

bioinformatics↗

bioRxiv2023

Cytosolic retention of the mitochondrial protease HtrA2 during mitochondrial protein import stress (MPIS) triggers the DELE1-HRI pathway

Mitochondrial stress inducers, such as the proton ionophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and the ATPase pump inhibitor oligomycin, trigger the DELE1-HRI branch of the integrated stress response (ISR) pathway. Previous studies performed using epitope-tagged forms of DELE1 showed that these stresses induced the accumulation of a cleaved form of DELE1, DELE1-S, which stimulates HRI. Here, we report that mitochondrial protein import stress (MPIS) is an overarching stress that triggers the DELE1-HRI pathway, and that endogenous DELE1 could be cleaved into two forms, DELE1-S and DELE1-VS, the latter accumulating only upon non- depolarizing MPIS. We further showed that DELE1 specifically senses MPIS triggered by the inhibition of the TIM23 complex at the inner mitochondrial membrane (IMM). While MPIS can also cause mitophagy induction through engagement of the NLRX1-RRBP1 pathway, we observed that DELE1-HRI and NLRX1-RRBP1 signaling were engaged independently upon MPIS. Surprisingly, our results suggest that in our cellular model the mitochondrial protease OMA1 was dispensable for DELE1 cleavage upon MPIS. Instead, we identified a key role for another mitochondrial protease, HtrA2, in mediating the cleavage of DELE1 into DELE1-S and DELE1- VS. Our data further suggest that DELE1 is likely cleaved into DELE1-S by HtrA2 in the cytosol, while the DELE1-VS form might be generated during halted translocation of the protein into mitochondria. Together, this study identifies MPIS as the overarching stress detected by DELE1 and identifies HtrA2 as a critical protease involved in DELE1 processing.

cell biology↗

bioRxiv2020

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2 kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed -synuclein, a protein known to aggregate in Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded -synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to -synucleinopathies in humans where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

cell biology↗