The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress

Choi, Jin Sun; Djebbar, Sonia; Fournier, Andréa; Labrie, Claude

doi:10.1007/s12192-013-0471-6

Cited by 27 publications

(37 citation statements)

References 14 publications

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“…Possible differences in the transcriptional regulation between wt and Enu 1/1 mice were determined by mRNA quantification (RT‐qPCR). We measured the mRNA levels of Dnajc12 and Pah , as well as those for other selected genes based on their possible interactions with DNAJC12, including (i) the molecular chaperones Hsp70 ( Hspa1b ), Hsc70 ( Hspa8 ), HSF1 ( Hsf1 ), and BIP ( Hspa5 ), the latter being an endoplasmatic reticulum chaperone that is associated with DNAJC12 in situations of cellular stress (Choi et al., ), and the co‐chaperone/E3 ubiquitin‐protein ligase CHIP ( Stub1 ); (ii) the eukaryotic translation elongation factor 1 delta EEF1D ( Eef1d ), which has been found to interact with DNAJC12 in a transcription factor interaction network (Miyamoto‐Sato et al., ); (iii) the estrogen receptors 1 and 2 ESR1 and 2 ( Esr1 , Esr2 ), and the G protein‐coupled estrogen receptor 1 ( Gper1 ), which were analyzed because DNAJC12 expression has been associated with estrogen receptor status in breast cancers (De Bessa et al., ); and (iv) GTP cyclohydrolase 1 ( Gch1 ) and GTP cyclohydrolase 1 feedback regulatory protein ( Gchfr ), which are involved in the synthesis of the PAH‐cofactor tetrahydrobiopterin (BH 4 ). The results are presented in Table .…”

Section: Resultsmentioning

confidence: 99%

“…Possible differences in the transcriptional regulation between wt and Enu 1/1 mice were determined by mRNA quantification (RT-qPCR). We measured the mRNA levels of Dnajc12 and Pah, as well as those for other selected genes based on their possible interactions with DNAJC12, including (i) the molecular chaperones Hsp70 (Hspa1b), Hsc70 (Hspa8), HSF1 (Hsf1), and BIP (Hspa5), the latter being an endoplasmatic reticulum chaperone that is associated with DNAJC12 in situations of cellular stress (Choi et al, 2014), and the Gper1 was faintly expressed, and Hsp70 also showed low expression.…”

Section: Quantification Of Gene Expression Of Pah Dnajc12 and Assocmentioning

confidence: 99%

“…DNAJC12 and HSC70/HSP70 were detected in the whole lysate, nuclear, and cytosolic fractions. The purity of the fractions was tested with lamin beta1 (nuclear fraction marker) and GAPDH (cytosolic fraction marker) DNAJC12 is mainly a cytoplasmic protein with a minor nuclear localization(Choi, Djebbar, Fournier, & Labrie, 2014), and since nuclear proteins are often poorly detected in whole tissue lysates, we investigated whether a different cytoplasmic/nuclear distribution of DNAJC12 in the normal and HPA mice could explain the different immunodetected levels. The liver lysates of wt, heterozygous Enu 1/wt , and Enu 1/1 were fractionated into cytosolic and nuclear fractions prior to the SDS-PAGE and immunodetection.…”

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confidence: 99%

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Phenylalanine hydroxylase variants interact with the co‐chaperone DNAJC12

et al. 2019

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DNAJC12, a type III member of the HSP40/DNAJ family, has been identified as the specific co‐chaperone of phenylalanine hydroxylase (PAH) and the other aromatic amino acid hydroxylases. DNAJ proteins work together with molecular chaperones of the HSP70 family to assist in proper folding and maintenance of intracellular stability of their clients. Autosomal recessive mutations in DNAJC12 were found to reduce PAH levels, leading to hyperphenylalaninemia (HPA) in patients without mutations in PAH. In this work, we investigated the interaction of normal wild‐type DNAJC12 with mutant PAH in cells expressing several PAH variants associated with HPA in humans, as well as in the Enu1/1 mouse model, homozygous for the V106A‐Pah variant, which leads to severe protein instability, accelerated PAH degradation and mild HPA. We found that mutant PAH exhibits increased ubiquitination, instability, and aggregation compared with normal PAH. In mouse liver lysates, we showed that DNAJC12 interacts with monoubiquitin‐tagged PAH. This form represented a major fraction of PAH in the Enu1/1 but was also present in liver of wild‐type PAH mice. Our results support a role of DNAJC12 in the processing of misfolded ubiquitinated PAH by the ubiquitin‐dependent proteasome/autophagy systems and add to the evidence that the DNAJ proteins are important players both for proper folding and degradation of their clients.

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Section: Resultsmentioning

confidence: 99%

Section: Quantification Of Gene Expression Of Pah Dnajc12 and Assocmentioning

confidence: 99%

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confidence: 99%

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Phenylalanine hydroxylase variants interact with the co‐chaperone DNAJC12

et al. 2019

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“…Lower CSF 5-HIAA compared to CSF HVA levels could be associated with a stronger interaction between DNAJC12 and tryptophan hydroxylase. DNAJC12 interacts with an additional 44 proteins, 21 of which are localized in the mitochondria, suggesting that DNAJC12 might have an important role in the mitochondrial process [8]. Pyruvate carboxylase, a key regulator of tricarboxylic acid cycle, was the most commonly identified mitochondrial protein interacting with DNAJC12 [8].…”

Section: Discussionmentioning

confidence: 99%

“…DNAJC12 interacts with an additional 44 proteins, 21 of which are localized in the mitochondria, suggesting that DNAJC12 might have an important role in the mitochondrial process [8]. Pyruvate carboxylase, a key regulator of tricarboxylic acid cycle, was the most commonly identified mitochondrial protein interacting with DNAJC12 [8]. A wider range of clinical and biochemical phenotypes may be associated with DNAJC12 variants in the future.…”

Section: Discussionmentioning

confidence: 99%

DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome sequencing re-analysis

et al. 2018

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Hyperphenylalaninemia, movement disorder, and intellectual disability due to variants in DNAJC12 is a recently reported inherited neurotransmitter disorder. We report two new patients with this new genetic disorder. Patient 1 is a 6-year-11-month-old boy with mild hyperphenylalaninemia and global developmental delay (GDD). Seventeen-year-old male sibling of patient 1 had GDD from the first year of life. He had mild hyperphenylalaninemia at 11.5 years of age following his younger brother's diagnosis. He had low levels of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid. Whole-exome sequencing (WES) was normal in 2016. After the first description of DNAJC12-associated hyperphenylalaninemia, dystonia, and intellectual disability in 2017, WES re-analysis identified a homozygous c.58_59delGG (p.(Gly20Metfs*2)) variant in DNAJC12. His younger brother was homozygous for the same variant, confirming the diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability. Mild hyperphenylalaninemia and GDD should warrant targeted DNAJC12 genetic testing for the early diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability.

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Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia

et al. 2020

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Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298‐2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation‐specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation‐specific treatments for PKU.

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The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress

Cited by 27 publications

References 14 publications

Phenylalanine hydroxylase variants interact with the co‐chaperone DNAJC12

Phenylalanine hydroxylase variants interact with the co‐chaperone DNAJC12

DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome sequencing re-analysis

Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia

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