DNAJC17 is localized in nuclear speckles and interacts with splicing machinery components

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.

Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment

“…These include the closely linked dual oxidase genes Duox1 and Duox2, and the dual oxidase maturation factor Duoxa2 that map within a 68 kb interval. Another candidate gene located 3.1 Mb proximal, Dnajc17, encodes a type III heat-shock protein-40 involved in splicing, which has been suggested as a candidate for Htrc2 (Pascarella et al 2018). This gene is hypothesized to be the modifier of thyroid gland development and function in Nkx2.1, Pax8 double heterozygotes and affects Tg transcription in cell culture (Amendola et al 2010).…”

Aflibercept Intervention in Experimental Branch Retinal Vein Occlusion Results in Upregulation of DnaJ Homolog Subfamily C Member 17

“…The proteins with largest regulations included DNAJC17 and possibly NDRG2. DNAJC17 is a heat shock protein family member known to be involved in splicing-related processes [ 33 ], but the function of DNAJC17 remains largely unknown [ 33 ]. DNAJC17 belongs to a class of cofactors called J-proteins.…”

Coordination of RNA Processing Regulation by Signal Transduction Pathways

“…Since pharmacologic inhibition of HSP90 blocked the re-phosphorylation of SRSF10 and the recovery of splicing after heat shock, HSP90 is also likely necessary for this process [164]. Subsequent studies confirmed the role of HSP27 in splicing regulation and showed that a large number of genes are susceptible to HSP27 depletion [165].…”