Prefoldin Function in Cellular Protein Homeostasis and Human Diseases

Cellular functions are largely performed by proteins. Defects in the production, folding, or removal of proteins from the cell lead to perturbations in cellular functions that can result in pathological conditions for the organism. In cells, molecular chaperones are part of a network of surveillance mechanisms that maintains a functional proteome. Chaperones are involved in the folding of newly synthesized polypeptides and assist in refolding misfolded proteins and guiding proteins for degradation. The present review focuses on the molecular co-chaperone prefoldin. Its canonical function in eukaryotes involves the transfer of newly synthesized polypeptides of cytoskeletal proteins to the tailless complex polypeptide 1 ring complex (TRiC/CCT) chaperonin which assists folding of the polypeptide chain in an energy-dependent manner. The canonical function of prefoldin is well established, but recent research suggests its broader function in the maintenance of protein homeostasis under physiological and pathological conditions. Interestingly, non-canonical functions were identified for the prefoldin complex and also for its individual subunits. We discuss the latest findings on the prefoldin complex and its subunits in the regulation of transcription and proteasome-dependent protein degradation and its role in neurological diseases, cancer, viral infections and rare anomalies.

β-Synuclein: An Enigmatic Protein with Diverse Functionality

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS.

Syndecan Regulates Cellular Morphogenesis in Cooperation with the Netrin Guidance Pathway and Rho-family GTPases

The establishment of complex cell shapes is essential for specific cellular functions, and thus critical in animal development and physiology. Heparan sulfate proteoglycans (HSPGs) are conserved glycoproteins that regulate interactions between extracellular signals and their receptors, to orchestrate morphogenetic events and elicit cellular responses. Although HSPG-regulated pathways have been implicated in regulating the guidance of neuronal migrations, whether HSPGs regulate earlier aspects of cellular development that dictate cell shape remains unknown. HSPGs consist of a protein core (e.g., Syndecan, Perlecan, Glypican, etc.) with attached heparan sulfate (HS) glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin family. Using mutations in the two C. elegans HS glycosyltransferases genes, rib-1 and rib-2, we reveal that HSPGs control the number of cellular projections in the epithelial excretory canal cell, which can form more than its normal four canals in these mutants. We identify SDN-1/Syndecan as the key HSPG that regulates the number of excretory canal cell projections in a cell-autonomous manner. We also find that Syndecan and guidance receptors for Netrin function in the same pathway to restrict the number of cellular projections. Furthermore, we show that the formation of extra projections in the absence of Syndecan requires the conserved Rho-family GTPases CED-10/Rac and MIG-2/RhoG. Our findings not only contribute to understanding the roles of conserved HSPGs in cellular morphogenetic events, but also reveal the existence of an HSPG-regulated system operating to guarantee that a precise number of cellular projections is established during cell development. Given the evolutionary conservation of developmental mechanisms and the molecules implicated, this work provides information relevant to understanding the cellular and molecular bases of the development of precise cellular morphologies in varied cell types across animals.

Peroxisome function relies on organelle-associated mRNA translation

Localized translation of peroxisomal membrane proteins is crucial for cellular functions.

Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Multifaceted Microcephaly-Related Gene MCPH1

MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1.

Proteasome granular localization is regulated through mitochondrial respiration and kinase signaling

In yeast, proteasomes are enriched in cell nuclei where they execute important cellular functions. Nutrient-stress can change this localization indicating proteasomes respond to the cell's metabolic state. However, the signals that connect these processes remain poorly understood. Carbon starvation triggers a reversible translocation of proteasomes to cytosolic condensates known as proteasome storage granules (PSGs). Surprisingly, we observed strongly reduced PSG levels when cells had active cellular respiration prior to starvation. This suggests the mitochondrial activity of cells is a determining factor in the response of proteasomes to carbon starvation. Consistent with this, upon inhibition of mitochondrial function we observed proteasomes relocalize to granules. These links between proteasomes and metabolism involve specific signaling pathways, as we identified a MAP kinase cascade that is critical to the formation of proteasome granules after respiratory growth but not following glycolytic growth. Furthermore, the yeast homolog of AMP kinase, Snf1, is important for proteasome granule formation induced by mitochondrial inhibitors, while dispensable for granule formation following carbon starvation. We propose a model where mitochondrial activity promotes proteasome nuclear localization.

Low-Molecular-Weight Heparin Enhanced Therapeutic Effects of Human Adipose-Derived Stem Cell Administration in a Mouse Model of Lupus Nephritis

BackgroundLupus nephritis is a life-threatening complication in systemic lupus erythematosus (SLE), but the efficiency of current therapies involving corticosteroids, immunosuppressants, and biological agents is limited. Adipose-derived mesenchymal stem cells (ASCs) are gaining attention as a novel treatment for inflammation in SLE. Low-molecular-weight heparin (LMWH) exhibits multiple functions including anti-inflammatory, anti-fibrotic, and cell function-promoting effects. LMWH stimulation is expected to increase the therapeutic effect of ASCs by promoting cellular functions. In this study, we investigated the effects of LMWH on ASC functions and the therapeutic effect of LMWH-activated human-ASCs (hep-hASCs) in an SLE mouse model.MethodsThe cellular functions of human-derived ASCs stimulated with different LMWH concentrations were observed, and the optimum LMWH dose was selected. The mice were assigned to control, human-ASC, and hep-hASC groups; treatments were performed on week 20. Twenty-six week-old mice were sacrificed, and urine protein score, serum blood urea nitrogen, creatinine (Cr), anti-ds DNA IgG antibody, and serum IL-6 levels were analyzed in each group. Mice kidneys were evaluated via histological examination, immunohistochemical staining, and gene expression levels.ResultsLMWH significantly promoted ASC migration and proliferation and hepatocyte growth factor production and upregulated immunomodulatory factors in vitro. Hep-hASC administration resulted in significant disease activity improvement including proteinuria, serum Cr and IL-6 levels, anti-ds DNA IgG antibody, glomerulonephritis, and immune complex in mice. Inflammation and fibrosis in kidneys was significantly suppressed in the hep-hASC group; the gene expression levels of TNF-alpha, TIMP-2, and MMP-2 was significantly downregulated in the hep-hASC group compared with the control group.ConclusionsHep-hASC exhibited higher anti-inflammatory and anti-fibrotic effects than hASCs and may be a candidate tool for SLE treatment in future.

New Insights into LINC00346 and its Role in Disease

Accumulating evidence has shown that long intergenic non-protein-coding RNA 346 (LINC00346) functions as an oncogene in the tumorigenesis of several cancers. The expression level of LINC00346 has been shown to be obviously correlated with prognosis, lymphoma metastasis, histological grade, TNM stage, tumor size and pathologic stage. LINC00346 has been found to regulate specific cellular functions by interacting with several molecules and signaling pathways. In this review, we summarize recent evidence concerning the role of LINC00346 in the occurrence and development of diseases. We also discuss the potential clinical utility of LINC00346, thereby providing new insight into the diagnosis and treatment of diseases. In addition, we further discuss the potential clinical utility of LINC00346 in the diagnosis, prognostication, and treatment of diseases.

Unifying Gene Expression Complexity and Cellular Operational Efficiency: Application of the Locality and Caching Principles via a Cell-to-Computer Analogy

Gene expression is time-consuming, and the delay from transcription activation to produced proteins is sequentially longer from bacteria to yeast and to humans. How human cells bypass the delay and attain operational efficiency, i.e., quick proteomic response to signals, is not well understood. The computer has endured the same system latency issue due to much slower information retrieval (hard drive (HD) to memory and to CPU) than CPU execution, and mitigated it via efficient memory management, namely, the spatiotemporal locality principles that control specialized user functions and the permanent caching of core system functions, the operating system (OS) kernel. Thus, in this study, we unified gene expression and HD-memory-CPU information flow as instances of the Shannon information theory, both supporting the respective system operations and consisting of three components: information storage, the execution/decoding step, and the channel for the dynamic storage-to-execution information flow; the gene expression machinery and their regulators, and the OS kernel, were deemed as the respective channels. This abstraction prompted a multi-omic comparative analysis, generating experimental evidence that transcriptome regulation shares the computer memory management principles. First, the temporal locality principle explains the mRNA stabilization-by-translation regulatory mechanism and controls specialized cellular functions. Second, the caching principle explains cytoplasmic mRNA sequestration and the defiance of the locality principle by highly sequestered mRNAs. Third, strikingly, in both systems, the caching principle controls the information channels; similar to permanent caching of OS kernel, basic translation/transcription machinery and their regulators are the top most sequestered mRNAs. Summarily, the locality and the caching principles differentially regulate specialized functions and core system functions, respectively, integrating the complexity of transcriptome regulation with cellular operational latency mitigation.