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Review
. 2021 Oct 15;24(11):103273.
doi: 10.1016/j.isci.2021.103273. eCollection 2021 Nov 19.

A comprehensive analysis of prefoldins and their implication in cancer

Irene Herranz-Montoya  1 , Solip Park  2 , Nabil Djouder  1
Affiliations
Review

A comprehensive analysis of prefoldins and their implication in cancer

Irene Herranz-Montoya et al. iScience. .

Abstract

Prefoldins (PFDNs) are evolutionary conserved co-chaperones, initially discovered in archaea but universally present in eukaryotes. PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins. Unlike the eukaryotic PFDNs which interact with cytoskeletal components, the archaeal PFDNs can bind and stabilize a wide range of substrates, possibly due to their great structural diversity. The discovery of the unconventional RPB5 interactor (URI) PFDN-like complex (UPC) suggests that PFDNs have versatile functions and are required for different cellular processes, including an important role in cancer. Here, we summarize their functions across different species. Moreover, a comprehensive analysis of PFDNs genomic alterations across cancer types by using large-scale cancer genomic data indicates that PFDNs are a new class of non-mutated proteins significantly overexpressed in some cancer types.

Keywords: Biological sciences; Cancer; Cell biology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Structure of PFDN (A–C) Schematic representation of the structure of PFDN in Archaea (A), of the classic PFDN complex in eukaryotes (B) and of the eukaryotic UPC (C). Two α (in green) and four β-class (in blue) PFDNs assemble through hydrophobic interactions to form a jellyfish-like structure, as evidenced by x-ray crystallography analyses performed in Archaea. Similar structural model has been proposed for the classic eukaryotic PFDN complex. Yet, the structure of the UPC remains to be determined.
Figure 2
Figure 2
Functions of PFDNs in Archaea Archaea present two different PFDNs, α and β, which assemble in a 2α4β ratio to form the classic PFDN complex. This complex binds to nascent unfolded proteins to deliver them to the CCT class II chaperonin to complete their folding. The classic PFDN complex also has intrinsic folding properties and can bind to a range of proteins to prevent their aggregation.
Figure 3
Figure 3
Functions of PFDNs in budding yeast In budding yeast, the classic PFDN complex is formed by proteins Gim1 to Gim 5 and PFDN1. This complex binds to nascent cytoskeletal proteins, such as actin and tubulin, to deliver them to the chaperonin CCT where they complete their folding. It also binds to misfolded proteins to promote their degradation through the delivery to the proteasome machinery. Some components of the complex are also involved in nuclear regulation of gene expression. Yeast presents an atypical PFDN termed Bud27 which is not forming part of any PFDN complex in these organisms. Bud27 also contributes to protein folding by binding to HSP70. It also contributes to the biogenesis of the RNA polymerases I, II, and III thanks to its interaction with RPB5, a common component of the three of them; and to the assembly of the initiation of translation machinery. In the nucleus, Bud27 contributes to transcription elongation by interacting with the polymerases and with chromatin remodelling complexes such as RSC. Loss of URI also increases DNA damage.
Figure 4
Figure 4
Role of PFDNs in mammals In mammals, the classic PFDN complex is formed by PFDNs 1 to 6. As in yeasts, it binds to nascent actin and tubulin cytoskeletal proteins to deliver them to the chaperonin CCT to promote their folding. The chaperone activity of the complex has been also associated to proteins involved in neurodegenerative diseases, such as Aβ oligomers, α-synuclein, or huntingtin (HTT). Apart from these functions within the complex, PFDN 3 is also involved in the stabilization of pVHL; and PFDN 5 has been associated with lipid metabolism. Mammals also present the unconventional or URI PFDN-like complex (UPC). It is involved in chromatin remodelling functions, for example by binding KAP1 and PPA2 together to allow the regulation of the histone deacetylase HDAC1. UPC also binds to the R2TP module to form a complex termed PAQosome that has been involved in the assembly of other protein complexes, such as the RNA polymerases, L7Ae snoRNP family of ribonucleoproteins, or PIKKs through the interaction with the TTT complex. The PAQosome is also involved in protein folding since it interacts with the chaperones HSP70 and 90, and is related to other cellular processes such as inhibition of mTOR through interaction with the TSC complex or the cilia function though its interaction with dynein. In the nucleus, the PAQosome promotes transcription elongation by its interaction with the polymerases and with chromatin remodeling complexes such as RSC. The UPC component URI has also shown other functions besides its contribution to the UPC. URI affects cell survival thanks to its relationship with PP1γ, and also cell proliferation by binding to β-catenin and thus preventing its translocation to the nucleus to promote cell proliferation and by affecting O-Glucosyl N-Acetylation of proteins like c-Myc by its PKA-dependent interaction with OGT. Furthermore, loss of URI has been associated with an increase in DNA damage, at least in part by binding to AhR and ER receptors and thus affecting NAD+ metabolism. URI binding to these receptors also affects insulin production in β-cells in the pancreas. URI also affects chromatin remodeling in the nucleus by interacting with parafibromin and PAF1. The other alfa protein forming the UPC, STAP1, is also involved in other functions beyond the UPC, for example in NF-κB signaling.
Figure 5
Figure 5
Gene expression level of PFDNs across tissues in humans Heatmap showing the gene expression of the 9 PFDN genes in different human tissues. Gene expression levels are from 29 human tissues from GTEx Project data V8. Presented values are the mean of log10-transformed Transcript Per Million (TPM) of samples in each tissue.
Figure 6
Figure 6
Genome aberrations of PFDN genes in cancer (A) Barplot showing the percentage of patients with genomic aberrations (amplifications in red, deletions in blue and single mutations in green) in the PFDN genes in the different cancer types. (B)URI, PFDN2 and PFDN4r are the PFDN genes found in a higher number of cancer types with an important percentage of patients with genomic aberrations (CNVs and mutations) in these genes. CNV, Copy Number Variation.
Figure 7
Figure 7
PFDNs are upregulated in cancer at mRNA level Heatmap showing the log 2 of the fold change in mRNA levels of PFDNs in cancer tissues compared to adjacent normal tissue, as computed using moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 across different cancer types of TCGA. Stars represent the adjusted p value associated to the change assessed by the Wald test after normalization of RNA-seq counts (∗∗∗ = p < 0.005; ∗∗ = p < 0.01; ∗ = p < 0.05). PFDN rows are displayed according to clustering analysis of the log2FC. TCGA, The Cancer Genome Atlas; UPC, Unconventional PFDN-like Complex; FC, Fold Change
Figure 8
Figure 8
PFDNs contribute to cellular adaptive responses to stress Different pathology-related environmental factors disrupt cellular functions, thus inducing a cellular response in order to restore homeostasis. PFDNs contribute to this cellular buffering response, either by their functions as PFDN complexes (classic or UPC) or by their actions as single proteins, as demonstrated for URI. PFDNs ensure a proper protein folding, as well as a proper regulation of cell cycle and survival, thus contributing to restore cellular homeostasis. When PFDNs' buffering activities are not enough to compensate the stress or when PFDN protein levels are altered, cell functions result dysregulated, leading to different pathological conditions.
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