Biology subjects

Carra, S.

Publications and source records attributed to Carra, S..

3 recordsLinked to original sources

bioRxiv2020

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNA-sequencing profiles to analyze the expression and organization of chaperones across 29 main tissues. We found that relative to protein-coding genes, chaperones were significantly more ubiquitously and highly expressed across all tissues. Nevertheless, differential expression analysis revealed that most chaperones were up- or down-regulated in certain tissues, suggesting that they have tissue-specific roles. In agreement, chaperones that were upregulated in skeletal muscle were highly enriched in mouse myoblasts and in nematodes muscle tissue, and overlapped significantly with chaperones that are causal for muscle diseases. We also identified a distinct subset of chaperones that formed a uniformly-expressed, cross-family core group conducting basic cellular functions that was significantly more essential for cell survival. Altogether, this suggests a layered architecture of chaperones across tissues that is composed of shared core elements that are complemented by variable elements which give rise to tissue-specific functions and sensitivities, thereby contributing to the tissue-specificity of protein misfolding diseases. Significance StatementProtein misfolding diseases, such as neurodegenerative disorders and myopathies, are often manifested in a specific tissue or even a specific cell type. Enigmatically, however, they are typically caused by mutations in widely expressed proteins. Here we focused on chaperones, the main and basic components of the protein-folding machinery of cells. Computational analyses of large scale tissue transcriptomes unveils that the chaperone system is composed of core essential elements that are uniformly expressed across tissues, and of variable elements that are differentially expressed in a tissue-specific manner. This organization allows each tissue to fit the quality control system to its specific requirements and illuminates the mechanisms that underlie a tissues susceptibility to protein-misfolding diseases.

systems biology↗

bioRxiv2019

BAG3 Pro209 mutants associated with myopathy and neuropathy sequester chaperones of the CASA-complex in aggresomes

Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2-associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6- and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 led to a relocation of other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so-called chaperone-assisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis.

cell biology↗

bioRxiv2019

Protein products of non-stop mRNA disrupt nucleolar homeostasis

Mutations that cause ribosome stalling or impair the cells protective response to stalling have been demonstrated to cause neurodegeneration, yet the mechanisms underlying these pathologies remain poorly understood. Here we investigated the fate of defective proteins translated from stall-inducing, nonstop mRNA that escape ubiquitylation by the Ribosome-associated Quality Control (RQC) E3 ligase LTN1. We found that nonstop protein products accumulated in nucleoli and this localization was driven by polylysine tracts produced by translation of the poly(A) tail of nonstop mRNA. Nucleolar sequestration increased the solubility of invading proteins but disrupted nucleoli, altering their dynamics, morphology, and resistance to stress. Changes in nucleolar morphology are consistent with a simple physical model in which LTN1 impairment enhances the inter-molecular interactions of nucleolar components. Our work elucidates how failure to degrade the protein products of stalled translation may affect distal cellular processes and will inform studies on the pathology of neurodegenerative disease.

cell biology↗