The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress

Napoletano, Francesco; Bravo, Gloria Ferrari; Voto, Ilaria Anna Pia; Santin, Aurora; Celora, Lucia; Campaner, Elena; Dezi, Clara; Bertossi, Arianna; Valentino, Elena; Santorsola, Mariangela; Rustighi, Alessandra; Fajner, Valentina; Maspero, Elena; Ansaloni, Federico; Cancila, Valeria; Valenti, Cesare; Santo, Manuela; Artimagnella, Osvaldo Basilio; Finaurini, Sara; Gioia, Ubaldo; Polo, Simona; Sanges, Remo; Tripodo, Claudio; Mallamaci, Antonello; Gustincich, Stefano; Fagagna, Fabrizio d’Adda di; Mantovani, Fiamma; Specchia, Valeria; Sal, Giannino Del

doi:10.1016/j.celrep.2021.109694

Cited by 20 publications

(8 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unravelling the mechanism of PIN1 complex formation with L1 ORF1p may reveal novel therapeutic avenues. Recently, Napoletano et al have demonstrated the role of PIN1 in the negative regulation of transposable elements including L1 transcripts in neurons during ageing or mechanical stress as PIN1 is essential for nuclear envelope integrity and heterochromatin maintenance [ 61 ]. However, in spite of high PIN1 expression in cancer cells, L1 expression is also upregulated, indicating dysregulation of other L1 regulatory mechanisms independent of PIN1 or reduced PIN1 nuclear activity in the presence of L1 ORF1.…”

Section: Discussionmentioning

confidence: 99%

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

et al. 2023

View full text Add to dashboard Cite

Background Molecular characterisation of hepatocellular carcinoma (HCC) is central to the development of novel therapeutic strategies for the disease. We have previously demonstrated mutagenic consequences of Long-Interspersed Nuclear Element-1 (LINE1s/L1) retrotransposition. However, the role of L1 in HCC, besides somatic mutagenesis, is not well understood. Methods We analysed L1 expression in the TCGA-HCC RNAseq dataset (n = 372) and explored potential relationships between L1 expression and clinical features. The findings were confirmed by immunohistochemical (IHC) analysis of an independent human HCC cohort (n = 48) and functional mechanisms explored using in vitro and in vivo model systems. Results We observed positive associations between L1 and activated TGFβ-signalling, TP53 mutation, alpha-fetoprotein and tumour invasion. IHC confirmed a positive association between pSMAD3, a surrogate for TGFβ-signalling status, and L1 ORF1p (P < 0.0001, n = 32). Experimental modulation of L1 ORF1p levels revealed an influence of L1 ORF1p on key hepatocarcinogenesis-related pathways. Reduction in cell migration and invasive capacity was observed upon L1 ORF1 knockdown, both in vitro and in vivo. In particular, L1 ORF1p increased PIN1 cytoplasmic localisation. Blocking PIN1 activity abrogated L1 ORF1p-induced NF-κB-mediated inflammatory response genes while further activated TGFβ-signalling confirming differential alteration of PIN1 activity in cellular compartments by L1 ORF1p. Discussion Our data demonstrate a causal link between L1 ORF1p and key oncogenic pathways mediated by PIN1, presenting a novel therapeutic avenue.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The correlation analysis of epigenetic terms showed a positive correlation only with proAD, as expected, whereas a negative correlation and no regulation were observed in the posAD and defAD stages, respectively. The Tau-dependent alteration of chromatin remodelling pathways associated with the proAD stage indicates an early modification of chromatin structures (Eissenberg and Elgin, 2014; El Hajjar et al, 2019; Frost et al, 2014; Napoletano et al, 2021). The reductions in the levels of heterochromatin markers, HP1α and H3K9me3, in the proAD-mimic model indicated Tau as a major factor leading to the loss of heterochromatin.…”

Section: Discussionmentioning

confidence: 99%

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer’s disease

Siano,

Varisco,

Terrigno

et al. 2023

Preprint

View full text Add to dashboard Cite

Recent research revealed that Tau plays critical roles in various neuronal functions. Our previous work demonstrated that destabilization and nuclear delocalization of Tau can alter the expression of glutamatergic genes, thereby mediating early neuronal damage.Upon analysing gene coexpression of AD temporal regions at different stages and the transcriptional output in differentiated neuroblastoma cells, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human AD temporal region showed that the Tau-dependent modulation of gene expression closely resembles an intermediate stage of AD that precedes the definitive AD condition. Furthermore, we identified the chromatin remodelling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers.We propose that Tau is able to globally affect the neuronal transcriptome and that its availability is linked to changes in gene expression during intermediate stages of AD development. In addition, we found that the epigenetic pathway is strongly affected by Tau during the progression of AD.

show abstract

“…A study using HCMV-infected fibroblasts showed that Pin1 binds to pSer22-Pro of lamin A and promotes the disintegration of the nuclear membrane by modulating the conformation of lamin [ 33 ]. Furthermore, it has been reported that Pin1 is essential for the maintenance of the structure of nuclear B-type lamin and the anchoring function of heterochromatin protein 1α, playing a role in preventing alterations in the nuclear membrane and relaxation of the heterochromatin [ 34 ]. Based on these reports, we speculated that Pin1 binds to phosphorylated lamins and induces and promotes the disruption of the nuclear membrane in mouse oocytes.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Isomerase, Pin1, Controls Meiotic Progression in Mouse Oocytes

Hoshino

Uchida

2022

Cells

View full text Add to dashboard Cite

During meiotic maturation, accurate progression of meiosis is ensured by multiple protein kinases and by signal transduction pathways they are involved in. However, the mechanisms regulating the functions of phosphorylated proteins are unclear. Herein, we investigated the role of Pin1, a peptidyl-prolyl cis-trans isomerase family member that regulates protein functions by altering the structure of the peptide bond of proline in phosphorylated proteins in meiosis. First, we analyzed changes in the expression of Pin1 during meiotic maturation and found that although its levels were constant, its localization was dynamic in different stages of meiosis. Furthermore, we confirmed that the spindle rotates near the cortex when Pin1 is inhibited by juglone during meiotic maturation, resulting in an error in the extrusion of the first polar body. In Pin1−/− mice, frequent polar body extrusion errors were observed in ovulation, providing insights into the mechanism underlying the errors in the extrusion of the polar body. Although multiple factors and mechanisms might be involved, Pin1 functions in meiosis progression via actin- and microtubule-associated phosphorylated protein targets. Our results show that functional regulation of Pin1 is indispensable in oocyte production and should be considered while developing oocyte culture technologies for reproductive medicine and animal breeding.

show abstract

The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress

Cited by 20 publications

References 100 publications

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer’s disease

Prolyl Isomerase, Pin1, Controls Meiotic Progression in Mouse Oocytes

Contact Info

Product

Resources

About