Shuttling of the chaperones Unc45b and Hsp90a between the A band and the Z line of the myofibril

The formation of thick filaments in striated muscle involves the chaperones Hsp90a and Unc45. We show that Unc45b and Hsp90a, two zebrafish orthologues, colocalize with myosin during myofibrillogenesis and associate with the Z line when myofibril assembly is completed. In response to stress or damage to the myofiber, Unc45b and Hsp90a dissociate from the Z line and transiently associate with myosin. Although chaperone activity of Unc45b requires the full-length protein, only the central and Unc45-Cro1p-She4p domains are required to anchor it to the Z line, and multiple subdomains mediate association with nascent myosin. We propose that the Z line serves as a reservoir for chaperones, allowing a rapid mobilization in response to muscle damage. Our data are consistent with a differential affinity model as an explanation for the shuttling of the chaperones between the Z line and myosin

Whole transcriptome data analysis of zebrafish mutants affecting muscle development

Formation of the contractile myofibril of the skeletal muscle is a complex process which when perturbed leads to muscular dystrophy. Herein, we provide a mRNAseq dataset on three different zebrafish mutants affecting muscle organization during embryogenesis. These comprise the myosin folding chaperone unc45b (unc45b_/_), heat shock protein 90aa1.1 (hsp90aa1.1_/_) and the acetylcholine esterase (ache_/_) gene. The transcriptome analysis was performed in duplicate experiments at 72h post-fertilization (hpf) for all three mutants, with two additional times of development( 24hpf and 48 hpf) for unc45b_/_. A total of 20 samples were analyzed by hierarchical clustering for differential gene expression. The data from this study support the observation made in Etard et al. (2015) [1] (http://dx.doi.org/10.1186/s13059-015-0825-8) that a failure to fold myosin activates a unique transcriptional program in the skeletal muscles that isdifferent from that induced in stressed muscle cell

Loss of function of myosin chaperones triggers Hsf1-mediated transcriptional response in skeletal muscle cells

Quality of sequences obtained with CASAVA 1.8.1 (Illumina) workflow. PF reads passing Illumina chastity filter. (XLSX 46 kb

Melanosomes in pigmented epithelia maintain eye lens transparency during zebrafish embryonic development

Altered levels of trace elements are associated with increased oxidative stress that is eventually responsible for pathologic conditions. Oxidative stress has been proposed to be involved in eye diseases, including cataract formation. We visualized the distribution of metals and other trace elements in the eye of zebrafish embryos by micro X-ray fluorescence (mu-XRF) imaging. Many elements showed highest accumulation in the retinal pigment epithelium (RPE) of the zebrafish embryo. Knockdown of the zebrafish brown locus homologues tyrp1a/b eliminated accumulation of these elements in the RPE, indicating that they are bound by mature melanosomes. Furthermore, albino (slc45a2) mutants, which completely lack melanosomes, developed abnormal lens reflections similar to the congenital cataract caused by mutation of the myosin chaperon Unc45b, and an in situ spin trapping assay revealed increased oxidative stress in the lens of albino mutants. Finally transplanting a wildtype lens into an albino mutant background resulted in cataract formation. These data suggest that melanosomes in pigment epithelial cells protect the lens from oxidative stress during embryonic development, likely by buffering trace elements.Peer reviewe

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

The ubiquitin–proteasome system degrades ubiquitin‐modified proteins to maintain protein homeostasis and to control signalling. Whole‐genome sequencing of patients with severe deafness and early‐onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient\u27s fibroblasts was however unaffected. Nevertheless, patient\u27s cells 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 patient\u27s fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient\u27s cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development

Gazette de Bayonne, de Biarritz et du Pays basque

04 septembre 19241924/09/04.Appartient à l’ensemble documentaire : Aquit