Abstract
DNAJC17 is a heat shock protein (HSP40) family member, identified in mouse as susceptibility gene for congenital hypothyroidism. DNAJC17 knockout mouse embryos die prior to implantation. In humans, germline homozygous mutations in DNAJC17 have been found in syndromic retinal dystrophy patients, while heterozygous mutations represent candidate pathogenic events for myeloproliferative disorders. Despite widespread expression and involvement in human diseases, DNAJC17 function is still poorly understood. Herein, we have investigated its function through high-throughput transcriptomic and proteomic approaches. DNAJC17-depleted cells transcriptome highlighted genes involved in general functional categories, mainly related to gene expression. Conversely, DNAJC17 interactome can be classified in very specific functional networks, with the most enriched one including proteins involved in splicing. Furthermore, several splicing-related interactors, were independently validated by co-immunoprecipitation and in vivo co-localization. Accordingly, co-localization of DNAJC17 with SC35, a marker of nuclear speckles, further supported its interaction with spliceosomal components. Lastly, DNAJC17 up-regulation enhanced splicing efficiency of minigene reporter in live cells, while its knockdown induced perturbations of splicing efficiency at whole genome level, as demonstrated by specific analysis of RNAseq data. In conclusion, our study strongly suggests a role of DNAJC17 in splicing-related processes and provides support to its recognized essential function in early development.
Highlights
DnaJ proteins, known as Hsp40, are a set of highly conserved proteins typically acting as co-factors of Hsp70 molecular chaperones
These results suggest a pleiotropic effect of DNAJC17 on several general cellular functions, which may underlie its essential role during early embryogenesis3
Notwithstanding previous studies that identified Dnajc17 as a susceptibility gene for congenital hypothyroidism2 and demonstrated its wide expression in mouse since early embryogenesis, in which it plays an essential role in pre-implantation stages3, the molecular function of DNAJC17 protein is still elusive
Summary
DnaJ proteins, known as Hsp, are a set of highly conserved proteins typically acting as co-factors of Hsp molecular chaperones They drive functional specificity to the otherwise ubiquitous Hsp partners, either by targeting them at precise cell compartments, or by delivering specific clients to Hsp701. Dnajc belongs to group C, bearing the J domain at its N-terminal region and a RNA recognition motif (RRM) located at the protein C-terminus, (UniProt: www.uniprot.org). It was identified as modifier gene for congenital hypothyroidism (CH) with thyroid dysgenesis (TD) by genetic linkage analysis of a polygenic mouse model of CH with TD2,3. By introducing novel functional informations, this work complements preliminary data on its ortholog in yeast, which were obtained with gene deletion mutants, and confirmed the involvement of molecular chaperones in the splicing machinery at splicing speckles
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