Characterization of novel elongated Parvulin isoforms that are ubiquitously expressed in human tissues and originate from alternative transcription initiation

Mueller, Jonathan Wolf; Kessler, Daniel S.; Neumann, Daniel; Stratmann, Tina; Papatheodorou, Panagiotis; Hartmann-Fatu, Cristina; Bayer, Peter

doi:10.1186/1471-2199-7-9

Cited by 37 publications

(31 citation statements)

References 26 publications

(39 reference statements)

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“…The PPIase superfamily is further classified into four families: cyclophilins, FK506-binding proteins (FKBPs), parvulins, and protein Ser/ Thr phosphatase 2A (PP2A) activator (PTPA) (15). The human genome contains two parvulin genes, PIN1 and PIN4 (17)(18)(19). The product of PIN1, PPIase NIMA-interacting 1 (Pin1) protein, binds HBx via its SP motifs on HBx, thereby promoting hepatocarcinogenesis (20).…”

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confidence: 99%

“…PIN4 encodes two proteins via alternative transcription initiation: parvulin 14 (Par14) (13.8 kDa; 131 amino acids) and parvulin 17 (Par17) (16.6 kDa; 156 amino acids); the additional 25 amino acids in Par17 constitute an N-terminal amphipathic ␣-helix (see Fig. 2A) (19,21). The overlapping cellular functions of Par14 and Par17 include chro-matin remodeling, cell cycle progression, rRNA processing, and tubulin polymerization (22)(23)(24).…”

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confidence: 99%

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Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner

Saeed

Kim

Piracha

et al. 2019

J Virol

160

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The parvulin 14 (Par14) and parvulin 17 (Par17) proteins, which are both encoded by the PIN4 gene, play roles in protein folding, chromatin remodeling, DNA binding, ribosome biogenesis, and cell cycle progression. However, the effects of Par14 and Par17 on viral replication have never been explored. In this study, we found that, in the presence of HBx, either Par14 or Par17 could upregulate hepatitis B virus (HBV) replication, whereas in the absence of HBx, neither Par14 nor Par17 had any effect on replication. Overexpression of Par14/Par17 markedly increased the formation of covalently closed circular DNA (cccDNA), synthesis of HBV RNA and DNA, and virion secretion. Conversely, PIN4 knockdown significantly decreased HBV replication in HBV-transfected and -infected cells. Coimmunoprecipitation revealed that Par14/Par17 engaged in direct physical interactions with HBx in the cytoplasm, nucleus, and mitochondria, possibly mediated through substrate-binding residues on Par14/Par17 (E46/D74 and E71/D99, respectively) and conserved 19R20P-28R29P motifs on HBx. Furthermore, these interactions enhanced HBx stability, promoted HBx translocation to the nuclear and mitochondrial fractions, and increased HBV replication. Chromatin immunoprecipitation assays revealed that, in the presence of HBx, Par14/Par17 were efficiently recruited to cccDNA and promoted transcriptional activation via specific DNA-binding residues (S19/44). In contrast, in the absence of HBx, Par14/Par17 bound cccDNA only at the basal level and did not promote transcriptional activation. Taken together, our results demonstrate that Par14 and Par17 upregulate HBV RNA transcription and DNA synthesis, thereby increasing the HBV cccDNA level, through formation of the cccDNA-Par14/17-HBx complex. IMPORTANCE The HBx protein plays an essential regulatory role in HBV replication. We found that substrate-binding residues on the human parvulin peptidylprolyl cis/trans isomerase proteins Par14 and Par17 bound to conserved arginine-proline (RP) motifs on HBx in the cytoplasm, nucleus, and mitochondria. The HBx-Par14/Par17 interaction stabilized HBx; promoted its translocation to the nucleus and mitochondria; and stimulated multiple steps of HBV replication, including cccDNA formation, HBV RNA and DNA synthesis, and virion secretion. In addition, in the presence of HBx, the Par14 and Par17 proteins bound to cccDNA and promoted its transcriptional activation. Our results suggest that inhibition or knockdown of Par14 and Par17 may represent a novel therapeutic option against HBV infection.

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confidence: 99%

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confidence: 99%

Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner

Saeed

Kim

Piracha

et al. 2019

J Virol

160

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“…Molecular timer [202] Cancer neurodegeneration [151,154] 2 Par14 Mitochondrial 1 rRNA processing [203] Cell cycle progression [204] Chromatin remodeling [205] 3 Par17 Mitochondrial 1 Unknown [206] Information on FKBPs has been adapted from [6]; data for the cyclophilins have been adapted from [52] AH with PPIase activity. CsA is a cyclic peptide initially isolated from the fungus Tolypocladium inflatum in 1969 [51].…”

Section: Cyclosporin and Cyclophilinsmentioning

confidence: 99%

Unraveling the Role of Peptidyl-Prolyl Isomerases in Neurodegeneration

et al. 2011

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Immunophilins are a family of highly conserved proteins with a peptidyl-prolyl isomerase activity that binds immunosuppressive drugs such as FK506, cyclosporin A, and rapamycin. Immunophilins can be divided into two subfamilies, the cyclophilins, and the FK506 binding proteins (FKBPs). Next to the immunophilins, a third group of peptidyl-prolyl isomerases exist, the parvulins, which do not influence the immune system. The beneficial role of immunophilin ligands in neurodegenerative disease models has been known for more than a decade but remains largely unexplained in terms of molecular mechanisms. In this review, we summarize reported effects of parvulins, immunophilins, and their ligands in the context of neurodegeneration. We focus on the role of FKBP12 in Parkinson's disease and propose it as a novel drug target for therapy of Parkinson's disease.

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“…Both proteins are encoded by the gene PIN4 which is located on chromosome Xq13.1 within the human genome [ 8 ]. The PIN4 promoter is TATA-less and situated in a CpG island typical of housekeeping genes.…”

Section: Introductionmentioning

confidence: 99%

“…Par14 has an N-terminal basic region (aa 1–35) and a C-terminal PPIase domain (aa 36 – 131) [ 11 , 12 ]. Par17 is an elongated isoform of Par14 that resulted by alternative transcription initiation [ 8 , 13 ]. Whereas Par14 is already present in metazoans, Par17 is only expressed in cells of great apes, but not in those of other primates [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Human DNA-binding peptidyl-prolyl cis/trans isomerase Par14 is cell cycle dependently expressed and associates with chromatin in vivo

Saningong

Bayer

2015

BMC Biochemistry

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BackgroundPar14, a member of the parvulin family of peptidyl-prolyl cis-trans isomerases that is involved in rRNA processing, microtubule formation and the glucose metabolism and has been suggested to play a role in chromatin remodeling on basis of sequence and structural identities to HMG proteins. Par14 is enriched in the nucleus and binds to double-stranded DNA in vitro.ResultsBy means of sub-nuclear biochemical fractionations, we demonstrate that cellular Par14 is associated with chromatin 3-fold higher than with the nuclear matrix in vivo. Par14 is released from the chromatin fraction after treatment with DNase I and elutes at high NaCl concentrations from the nucleic acid-binding fraction. Using qRT-PCR and western blotting we demonstrate that Par14 is up-regulated during the S and G2/M phases in synchronised human foreskin fibroblasts cells.ConclusionIn the light of our results, Par14 can be described as an endogenous non-histone chromatin protein, which binds DNA in vivo. We propose that Par14 is involved in a DNA-dependent activity such as transcription.

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Characterization of novel elongated Parvulin isoforms that are ubiquitously expressed in human tissues and originate from alternative transcription initiation

Cited by 37 publications

References 26 publications

Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner

Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner

Unraveling the Role of Peptidyl-Prolyl Isomerases in Neurodegeneration

Human DNA-binding peptidyl-prolyl cis/trans isomerase Par14 is cell cycle dependently expressed and associates with chromatin in vivo

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