Functional Contributions of Prefoldin to Gene Expression

Payán-Bravo, Laura; Peñate, Xenia

doi:10.1007/978-3-030-00737-9_1

Cited by 13 publications

(10 citation statements)

References 63 publications

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“…2 C). Protein folding-associated modules included members of the prefoldin complex, which is involved in actin and tubulin folding, as well as in transcription elongation ( Payán-Bravo et al, 2018 ), and members of the GET complex, which promotes insertion of tail-anchored proteins into the ER membrane ( ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Andersson

Romero

Rodrigues

et al. 2021

Journal of Cell Science

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The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells, and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified yeast deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Andersson

Romero

Rodrigues

et al. 2021

Journal of Cell Science

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“…Canonical prefoldin shows a jellyfish-like structure and is composed of six different subunits (PFDN1 to 6). PFDNs also participate in processes that take place in the cell nucleus [10], including molecular events that contribute to gene regulation [11].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer

Peñate

Praena-Fernández

Pareja

et al. 2020

Cancers

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Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial–mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. First, the mRNA expression of 518 non-small cell LC (NSCLC) cases from The Cancer Genome Atlas (TCGA) database was evaluated. Patients with PFDN1 overexpression had lower overall survival (OS; 45 vs. 86 months; p = 0.034). We then assessed the impact of PFDN expression on outcome in 58 NSCLC patients with available tumor tissue samples. PFDN1, 3, and 5 overexpression were found in 38% (n = 22), 53% (n = 31), and 41% (n = 24) of tumor samples. PFDN1, 3, and 5 overexpression were significantly associated with lower OS, lower disease-free survival (DFS), and lower distant metastasis-free survival (DMFS) for PFDN1 and 3 with a trend for PFDN5. In multivariate analysis, PFDN5 retained significance for OS (hazard ratio (HR) 2.56; p = 0.007) and PFDN1 for DFS (HR 2.53; p = 0.010) and marginally for DMFS (HR 2.32; p = 0.053). Our results indicate that protein response markers, such as PFDN1, 3, and 5, may complement mRNA signatures and be useful for determining the most appropriate therapy for NSCLC patients.

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“…Prefoldin is well known for its cytoplasmic role in the co-translational folding of tubulin and actin monomers ( 1 , 33 ). Prefoldin has also been shown to play additional functions in the cell nucleus ( 4 , 34 ), including a positive role in transcription elongation and co-transcriptional chromatin dynamics across the yeast genome ( 6 ). The results described in this work extend this view as they show a general contribution of prefoldin to human gene expression by modulating co-transcriptional splicing.…”

Section: Discussionmentioning

confidence: 99%

Human prefoldin modulates co-transcriptional pre-mRNA splicing

Payán-Bravo

Fontalva

Peñate

et al. 2021

Nucleic Acids Research

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Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the co-translational folding of actin and tubulin monomers. Additional functions of prefoldin have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin perturbations provoked transcriptional alterations across the human genome. Severe pre-mRNA splicing defects were also detected, particularly after serum stimulation. We found impairment of co-transcriptional splicing during transcription elongation, which explains why the induction of long genes with a high number of introns was affected the most. We detected genome-wide prefoldin binding to transcribed genes and found that it correlated with the negative impact of prefoldin depletion on gene expression. Lack of prefoldin caused global decrease in Ser2 and Ser5 phosphorylation of the RNA polymerase II carboxy-terminal domain. It also reduced the recruitment of the CTD kinase CDK9 to transcribed genes, and the association of splicing factors PRP19 and U2AF65 to chromatin, which is known to depend on CTD phosphorylation. Altogether the reported results indicate that human prefoldin is able to act locally on the genome to modulate gene expression by influencing phosphorylation of elongating RNA polymerase II, and thereby regulating co-transcriptional splicing.

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Functional Contributions of Prefoldin to Gene Expression

Cited by 13 publications

References 63 publications

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer

Human prefoldin modulates co-transcriptional pre-mRNA splicing

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