A co-opted endogenous retroviral envelope promotes cell survival by controlling SLC31A1/CTR1-mediated copper transport and homeostasis

Copper is a critical element for eukaryotic life, involved in numerous cellular functions and in redox balance but it can be toxic in excess. Therefore, tight regulation of copper acquisition and homeostasis is essential for cell physiology and survival. Here, we identified a unique mechanism for cell survival involving the regulation of copper homeostasis by an endogenous retroviral (ERV) envelope glycoprotein called Refrex1. We show that extracellular copper sensing by cells increased Refrex1 expression, which in turn regulated copper acquisition through interaction with the main copper transporter SLC31A1/CTR1. Downmodulation of Refrex1 resulted in intracellular copper accumulation leading to ROS production and subsequent apoptosis, which could be reverted by copper chelator treatment. Our results demonstrate that Refrex1 has been co-opted for its ability to regulate copper entry through CTR1 interaction in order to limit copper excess for a proper redox balance, and suggests that other ERV may have similar metabolic functions among vertebrates.

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A clonal fresh water plants acquires transgenerational stress resistance under recurring copper excess

10.1101/2021.02.06.430033 ◽

2021 ◽

Author(s):

Meret Huber ◽

Saskia Gablenz ◽

Martin Höfer

Keyword(s):

Stress Responses ◽

Plant Ecology ◽

Copper Accumulation ◽

Plant Fitness ◽

Genetic Inheritance ◽

Spirodela Polyrhiza ◽

Transgenerational Plasticity ◽

Copper Excess ◽

Water Plants

ABSTRACTAlthough non-genetic inheritance is thought to play an important role in plant ecology and evolution, evidence for adaptive transgenerational plasticity is scarce. Here, we investigated the consequences of copper excess on offspring defences and fitness in the giant duckweed (Spirodela polyrhiza) across multiple asexual generations. We found that exposing large monoclonal populations (>10,000 individuals) for 30 generations to copper excess decreased plant fitness during the first few generations but increased their fitness in consecutive generations under recurring stress when plants were grown for 5 generations under control conditions prior recurring conditions. Similarly, propagating individual plants as single descendants for 5 or 10 generations under copper excess decreased plant fitness when 5 generations and improved plant fitness when 10 generations passed between initial and recurring stress; thus, transgenerational stress responses likely contributed to the observed variations in offspring fitness of long-term copper exposed populations. Fitness benefits under recurring stress were partially associated with avoidance of excessive copper accumulation, which in turn correlated with transgenerationally modified flavonoid concentrations. Taken together, these data demonstrate time-dependent adaptive transgenerational responses under recurring stress, which highlights the importance of non-genetic inheritance for plant ecology and evolution.

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Challenges in the Diagnosis of Magnesium Status

Nutrients ◽

10.3390/nu10091202 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1202 ◽

Cited By ~ 20

Author(s):

Jayme Workinger ◽

Robert. Doyle ◽

Jonathan Bortz

Keyword(s):

Mineral Content ◽

Magnesium Deficiency ◽

The Body ◽

Dietary Practices ◽

Disease States ◽

Metabolic Functions ◽

Magnesium Status ◽

Critical Mineral ◽

Unique Mechanism

Magnesium is a critical mineral in the human body and is involved in ~80% of known metabolic functions. It is currently estimated that 60% of adults do not achieve the average dietary intake (ADI) and 45% of Americans are magnesium deficient, a condition associated with disease states like hypertension, diabetes, and neurological disorders, to name a few. Magnesium deficiency can be attributed to common dietary practices, medications, and farming techniques, along with estimates that the mineral content of vegetables has declined by as much as 80–90% in the last 100 years. However, despite this mineral’s importance, it is poorly understood from several standpoints, not the least of which is its unique mechanism of absorption and sensitive compartmental handling in the body, making the determination of magnesium status difficult. The reliance on several popular sample assays has contributed to a great deal of confusion in the literature. This review will discuss causes of magnesium deficiency, absorption, handling, and compartmentalization in the body, highlighting the challenges this creates in determining magnesium status in both clinical and research settings.

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Regulation of murine copper homeostasis by members of the COMMD protein family

Disease Models & Mechanisms ◽

10.1242/dmm.045963 ◽

2020 ◽

Vol 14 (1) ◽

pp. dmm045963

Author(s):

Amika Singla ◽

Qing Chen ◽

Kohei Suzuki ◽

Jie Song ◽

Alina Fedoseienko ◽

...

Keyword(s):

Copper Homeostasis ◽

Copper Accumulation ◽

Copper Transporter ◽

Copper Excretion ◽

Copper Absorption ◽

Hepatic Copper ◽

High Copper ◽

Molecular Machinery ◽

And Function

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

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PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Nucleic Acids Research ◽

10.1093/nar/gkaa590 ◽

2020 ◽

Vol 48 (18) ◽

pp. 10015-10033 ◽

Cited By ~ 1

Author(s):

Lisa Aberle ◽

Annika Krüger ◽

Julia M Reber ◽

Michelle Lippmann ◽

Matthias Hufnagel ◽

...

Keyword(s):

Chain Length ◽

Cell Cycle Progression ◽

Protein Localization ◽

Biological Significance ◽

Genotoxic Stress ◽

Cell Physiology ◽

Cellular Functions ◽

Beneficial Effects ◽

Cellular Processes ◽

Mouse Tissues

Abstract Poly(ADP-ribosyl)ation regulates numerous cellular processes like genome maintenance and cell death, thus providing protective functions but also contributing to several pathological conditions. Poly(ADP-ribose) (PAR) molecules exhibit a remarkable heterogeneity in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To unravel structure-specific functions of PAR, we used PARP1 mutants producing PAR of different qualities, i.e. short and hypobranched (PARP1\G972R), short and moderately hyperbranched (PARP1\Y986S), or strongly hyperbranched PAR (PARP1\Y986H). By reconstituting HeLa PARP1 knockout cells, we demonstrate that PARP1\G972R negatively affects cellular endpoints, such as viability, cell cycle progression and genotoxic stress resistance. In contrast, PARP1\Y986S elicits only mild effects, suggesting that PAR branching compensates for short polymer length. Interestingly, PARP1\Y986H exhibits moderate beneficial effects on cell physiology. Furthermore, different PARP1 mutants have distinct effects on molecular processes, such as gene expression and protein localization dynamics of PARP1 itself, and of its downstream factor XRCC1. Finally, the biological relevance of PAR branching is emphasized by the fact that branching frequencies vary considerably during different phases of the DNA damage-induced PARylation reaction and between different mouse tissues. Taken together, this study reveals that PAR branching and chain length essentially affect cellular functions, which further supports the notion of a ‘PAR code’.

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Exchangeable Chaperone Modules Contribute to Specification of Type I and Type II Hsp40 Cellular Function

Molecular Biology of the Cell ◽

10.1091/mbc.e03-03-0146 ◽

2004 ◽

Vol 15 (2) ◽

pp. 761-773 ◽

Cited By ~ 71

Author(s):

Chun-Yang Fan ◽

Soojin Lee ◽

Hong-Yu Ren ◽

Douglas M. Cyr

Keyword(s):

In Vivo Studies ◽

Cell Physiology ◽

Type I ◽

Type Ii ◽

Cellular Functions ◽

Chaperone Function ◽

Sequence Identity ◽

Carboxyl Terminal ◽

High Degree

Hsp40 family members regulate Hsp70s ability to bind nonnative polypeptides and thereby play an essential role in cell physiology. Type I and type II Hsp40s, such as yeast Ydj1 and Sis1, form chaperone pairs with cytosolic Hsp70 Ssa1 that fold proteins with different efficiencies and carry out specific cellular functions. The mechanism by which Ydj1 and Sis1 specify Hsp70 functions is not clear. Ydj1 and Sis1 share a high degree of sequence identity in their amino and carboxyl terminal ends, but each contains a structurally unique and centrally located protein module that is implicated in chaperone function. To test whether the chaperone modules of Ydj1 and Sis1 function in the specification of Hsp70 action, we constructed a set of chimeric Hsp40s in which the chaperone domains of Ydj1 and Sis1 were swapped to form YSY and SYS. Purified SYS and YSY exhibited protein-folding activity and substrate specificity that mimicked that of Ydj1 and Sis1, respectively. In in vivo studies, YSY exhibited a gain of function and, unlike Ydj1, could complement the lethal phenotype of sis1Δ and facilitate maintenance of the prion [RNQ+]. Ydj1 and Sis1 contain exchangeable chaperone modules that assist in specification of Hsp70 function.

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Mvb12 Is a Novel Member of ESCRT-I Involved in Cargo Selection by the Multivesicular Body Pathway

Molecular Biology of the Cell ◽

10.1091/mbc.e06-07-0601 ◽

2007 ◽

Vol 18 (2) ◽

pp. 646-657 ◽

Cited By ~ 34

Author(s):

Andrea J. Oestreich ◽

Brian A. Davies ◽

Johanna A. Payne ◽

David J. Katzmann

Keyword(s):

Normal Cell ◽

Transmembrane Proteins ◽

Multivesicular Body ◽

Eukaryotic Cells ◽

Cell Physiology ◽

Cellular Functions ◽

Protein Loss ◽

Endosomal Sorting ◽

Vacuolar Protein ◽

Selection Of

The multivesicular body (MVB) sorting pathway impacts a variety of cellular functions in eukaryotic cells. Perhaps the best understood role for the MVB pathway is the degradation of transmembrane proteins within the lysosome. Regulation of cargo selection by this pathway is critically important for normal cell physiology, and recent advances in our understanding of this process have highlighted the endosomal sorting complexes required for transport (ESCRTs) as pivotal players in this reaction. To better understand the mechanisms of cargo selection during MVB sorting, we performed a genetic screen to identify novel factors required for cargo-specific selection by this pathway and identified the Mvb12 protein. Loss of Mvb12 function results in differential defects in the selection of MVB cargoes. A variety of analyses indicate that Mvb12 is a stable member of ESCRT-I, a heterologous complex involved in cargo selection by the MVB pathway. Phenotypes displayed upon loss of Mvb12 are distinct from those displayed by the previously described ESCRT-I subunits (vacuolar protein sorting 23, -28, and -37), suggesting a distinct function than these core subunits. These data support a model in which Mvb12 impacts the selection of MVB cargoes by modulating the cargo recognition capabilities of ESCRT-I.

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Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks

Biochemical Journal ◽

10.1042/bj20110892 ◽

2011 ◽

Vol 441 (1) ◽

pp. 1-21 ◽

Cited By ~ 552

Author(s):

Brian Magnuson ◽

Bilgen Ekim ◽

Diane C. Fingar

Keyword(s):

Ribosomal Protein ◽

Cell Metabolism ◽

Lipid Synthesis ◽

Cell Physiology ◽

Cellular Functions ◽

S6 Kinase ◽

Glucose Homoeostasis ◽

Ribosomal Protein S6 ◽

And Function ◽

Mtor Signalling

The ribosomal protein S6K (S6 kinase) represents an extensively studied effector of the TORC1 [TOR (target of rapamycin) complex 1], which possesses important yet incompletely defined roles in cellular and organismal physiology. TORC1 functions as an environmental sensor by integrating signals derived from diverse environmental cues to promote anabolic and inhibit catabolic cellular functions. mTORC1 (mammalian TORC1) phosphorylates and activates S6K1 and S6K2, whose first identified substrate was rpS6 (ribosomal protein S6), a component of the 40S ribosome. Studies over the past decade have uncovered a number of additional S6K1 substrates, revealing multiple levels at which the mTORC1–S6K1 axis regulates cell physiology. The results thus far indicate that the mTORC1–S6K1 axis controls fundamental cellular processes, including transcription, translation, protein and lipid synthesis, cell growth/size and cell metabolism. In the present review we summarize the regulation of S6Ks, their cellular substrates and functions, and their integration within rapidly expanding mTOR (mammalian TOR) signalling networks. Although our understanding of the role of mTORC1–S6K1 signalling in physiology remains in its infancy, evidence indicates that this signalling axis controls, at least in part, glucose homoeostasis, insulin sensitivity, adipocyte metabolism, body mass and energy balance, tissue and organ size, learning, memory and aging. As dysregulation of this signalling axis contributes to diverse disease states, improved understanding of S6K regulation and function within mTOR signalling networks may enable the development of novel therapeutics.

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Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

10.1101/2021.04.15.439900 ◽

2021 ◽

Author(s):

Gaurav V. Sarode ◽

Kari Neier ◽

Noreene M. Shibata ◽

Yuanjun Shen ◽

Dmitry A Goncharov ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Mouse Model ◽

Histone Acetylation ◽

Wilson Disease ◽

Metabolic Pathways ◽

Histone Deacetylases ◽

Copper Accumulation ◽

Copper Transporter ◽

Pathogenic Variants

AbstractThe pathogenesis of Wilson disease (WD) is multi-factorial, involving hepatic and brain copper accumulation due to pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior DNA methylation investigations in human WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD, including alterations in the histone deacetylase HDAC5. To test the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD, we investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in the Jackson Laboratory toxic milk (tx-j) mouse model of WD compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). HDAC5 levels significantly increased in 9-week tx-j livers after 8 days of HFD compared to chow. In 24-week tx-j livers, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were also affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4, HDAC5, H3K9ac, and H3K27ac levels to that of CH3 liver. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, with Pparα and Pparγ among the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.Significance StatementWilson disease is considered a monogenic disease caused by pathogenic variants in the ATP7B copper transporter, resulting in hepatic and brain copper accumulation. Given the lack of genotype-phenotype correlation, evidence of epigenetic and metabolic mechanisms regulating phenotype in patients and in animal models could explain the high phenotype variability observed in WD. In this study, we identify class IIa histone deacetylases as players involved in the epigenetic regulation of key metabolic pathways that can affect WD severity as well as targets sensitive to dietary modulations, which is an important characteristic for designing effective and feasible therapies. Understanding the epigenetic mechanisms in WD pathogenesis contributes to a better understanding of the phenotypic variability in WD and other common liver conditions.

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Redox Potential of Antioxidants in Cancer Progression and Prevention

Antioxidants ◽

10.3390/antiox9111156 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1156

Author(s):

Sajan George ◽

Heidi Abrahamse

Keyword(s):

Oxidative Stress ◽

Cancer Progression ◽

Natural Antioxidants ◽

Redox Balance ◽

Redox Status ◽

Enzyme Activation ◽

Metabolic Reprogramming ◽

Cellular Functions ◽

Cellular Redox ◽

The Right

The benevolent and detrimental effects of antioxidants are much debated in clinical trials and cancer research. Several antioxidant enzymes and molecules are overexpressed in oxidative stress conditions that can damage cellular proteins, lipids, and DNA. Natural antioxidants remove excess free radical intermediates by reducing hydrogen donors or quenching singlet oxygen and delaying oxidative reactions in actively growing cancer cells. These reducing agents have the potential to hinder cancer progression only when administered at the right proportions along with chemo-/radiotherapies. Antioxidants and enzymes affect signal transduction and energy metabolism pathways for the maintenance of cellular redox status. A decline in antioxidant capacity arising from genetic mutations may increase the mitochondrial flux of free radicals resulting in misfiring of cellular signalling pathways. Often, a metabolic reprogramming arising from these mutations in metabolic enzymes leads to the overproduction of so called ’oncometabolites’ in a state of ‘pseudohypoxia’. This can inactivate several of the intracellular molecules involved in epigenetic and redox regulations, thereby increasing oxidative stress giving rise to growth advantages for cancerous cells. Undeniably, these are cell-type and Reactive Oxygen Species (ROS) specific, which is manifested as changes in the enzyme activation, differences in gene expression, cellular functions as well as cell death mechanisms. Photodynamic therapy (PDT) using light-activated photosensitizing molecules that can regulate cellular redox balance in accordance with the changes in endogenous ROS production is a solution for many of these challenges in cancer therapy.

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