The metal ion transporter IRT1 is necessary for iron homeostasis and efficient photosynthesis in Arabidopsis thaliana

AbstractMany ion channels and transporters are regulated by ubiquitination mediated by the Nedd4 family of HECT-type ubiquitin ligases (E3s). These E3s commonly interact with substrates via their WW domains that bind to specific motifs in target proteins. However, not all potential targets of these E3s contain WW-binding motifs. Therefore, accessory proteins may mediate the interaction between Nedd4 family members and their targets. Here we report that the divalent metal ion transporter DMT1, the primary nonheme iron transporter in mammals, is regulated by ubiquitination mediated by the Nedd4 family member WWP2. DMT1 interacts with 2 WW domain-interacting proteins, Ndfip1 and Ndfip2, previously proposed to have roles in protein trafficking. This promotes DMT1 ubiquitination and degradation by WWP2. Consistent with these observations, Ndfip1−/− mice show increased DMT1 activity and a concomitant increase in hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. This novel mechanism of regulating iron homeostasis suggests that Ndfips and WWP2 may contribute to diseases involving aberrant iron transport.

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Faculty Opinions recommendation of Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13353961.14725059 ◽

2011 ◽

Author(s):

Richard J Naftalin

Keyword(s):

Functional Properties ◽

Cellular Uptake ◽

Metal Ion ◽

Ion Transporter ◽

Broad Scope

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Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium

Archives of Toxicology ◽

10.1007/s00204-021-03106-z ◽

2021 ◽

Author(s):

Stephanie Probst ◽

Johannes Fels ◽

Bettina Scharner ◽

Natascha A. Wolff ◽

Eleni Roussa ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cell Fate ◽

Catalase Activity ◽

Metal Ion ◽

Iron Homeostasis ◽

Collecting Duct ◽

Duct Cell ◽

Plasmid Transfection

AbstractThe liver hormone hepcidin regulates systemic iron homeostasis. Hepcidin is also expressed by the kidney, but exclusively in distal nephron segments. Several studies suggest hepcidin protects against kidney damage involving Fe2+ overload. The nephrotoxic non-essential metal ion Cd2+ can displace Fe2+ from cellular biomolecules, causing oxidative stress and cell death. The role of hepcidin in Fe2+ and Cd2+ toxicity was assessed in mouse renal cortical [mCCD(cl.1)] and inner medullary [mIMCD3] collecting duct cell lines. Cells were exposed to equipotent Cd2+ (0.5–5 μmol/l) and/or Fe2+ (50–100 μmol/l) for 4–24 h. Hepcidin (Hamp1) was transiently silenced by RNAi or overexpressed by plasmid transfection. Hepcidin or catalase expression were evaluated by RT-PCR, qPCR, immunoblotting or immunofluorescence microscopy, and cell fate by MTT, apoptosis and necrosis assays. Reactive oxygen species (ROS) were detected using CellROX™ Green and catalase activity by fluorometry. Hepcidin upregulation protected against Fe2+-induced mIMCD3 cell death by increasing catalase activity and reducing ROS, but exacerbated Cd2+-induced catalase dysfunction, increasing ROS and cell death. Opposite effects were observed with Hamp1 siRNA. Similar to Hamp1 silencing, increased intracellular Fe2+ prevented Cd2+ damage, ROS formation and catalase disruption whereas chelation of intracellular Fe2+ with desferrioxamine augmented Cd2+ damage, corresponding to hepcidin upregulation. Comparable effects were observed in mCCD(cl.1) cells, indicating equivalent functions of renal hepcidin in different collecting duct segments. In conclusion, hepcidin likely binds Fe2+, but not Cd2+. Because Fe2+ and Cd2+ compete for functional binding sites in proteins, hepcidin affects their free metal ion pools and differentially impacts downstream processes and cell fate.

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IRON MAN interacts with BRUTUS to maintain iron homeostasis in Arabidopsis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2109063118 ◽

2021 ◽

Vol 118 (39) ◽

pp. e2109063118

Author(s):

Yang Li ◽

Cheng Kai Lu ◽

Chen Yang Li ◽

Ri Hua Lei ◽

Meng Na Pu ◽

...

Keyword(s):

Arabidopsis Thaliana ◽

Transcription Factors ◽

Iron Homeostasis ◽

Fe Deficiency ◽

Small Peptides ◽

Interaction Domain ◽

C Terminus ◽

Positive Regulators ◽

Fe Homeostasis ◽

And Function

IRON MAN (IMA) peptides, a family of small peptides, control iron (Fe) transport in plants, but their roles in Fe signaling remain unclear. BRUTUS (BTS) is a potential Fe sensor that negatively regulates Fe homeostasis by promoting the ubiquitin-mediated degradation of bHLH105 and bHLH115, two positive regulators of the Fe deficiency response. Here, we show that IMA peptides interact with BTS. The C-terminal parts of IMA peptides contain a conserved BTS interaction domain (BID) that is responsible for their interaction with the C terminus of BTS. Arabidopsis thaliana plants constitutively expressing IMA genes phenocopy the bts-2 mutant. Moreover, IMA peptides are ubiquitinated and degraded by BTS. bHLH105 and bHLH115 also share a BID, which accounts for their interaction with BTS. IMA peptides compete with bHLH105/bHLH115 for interaction with BTS, thereby inhibiting the degradation of these transcription factors by BTS. Genetic analyses suggest that bHLH105/bHLH115 and IMA3 have additive roles and function downstream of BTS. Moreover, the transcription of both BTS and IMA3 is activated directly by bHLH105 and bHLH115 under Fe-deficient conditions. Our findings provide a conceptual framework for understanding the regulation of Fe homeostasis: IMA peptides protect bHLH105/bHLH115 from degradation by sequestering BTS, thereby activating the Fe deficiency response.

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Wheat TaVIT2D restores phenotype and mediates iron homeostasis during growth of Arabidopsis thaliana in iron-deficient conditions

Plant Physiology Reports ◽

10.1007/s40502-018-0426-0 ◽

2018 ◽

Vol 24 (1) ◽

pp. 24-34

Author(s):

Raja Jeet ◽

Sudhir P. Singh ◽

Siddharth Tiwari ◽

Promila Pathak

Keyword(s):

Arabidopsis Thaliana ◽

Iron Homeostasis ◽

Iron Deficient

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Integrating naive Bayes models and external knowledge to examine copper and iron homeostasis in S. cerevisiae

Physiological Genomics ◽

10.1152/physiolgenomics.2000.4.2.127 ◽

2000 ◽

Vol 4 (2) ◽

pp. 127-135 ◽

Cited By ~ 24

Author(s):

E. J. Moler ◽

D. C. Radisky ◽

I. S. Mian

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Metal Ion ◽

Iron Homeostasis ◽

Graphical Model ◽

Naive Bayes ◽

Naïve Bayes ◽

Diauxic Shift ◽

Ion Regulation ◽

External Knowledge

A novel suite of analytical techniques and visualization tools are applied to 78 published transcription profiling experiments monitoring 5,687 Saccharomyces cerevisiae genes in studies examining cell cycle, responses to stress, and diauxic shift. A naive Bayes model discovered and characterized 45 classes of gene profile vectors. An enrichment measure quantified the association between these classes and specific external knowledge defined by four sets of categories to which genes can be assigned: 106 protein functions, 5 stages of the cell cycle, 265 transcription factors, and 16 chromosomal locations. Many of the 38 genes in class 42 are known to play roles in copper and iron homeostasis. The 17 uncharacterized open reading frames in this class may be involved in similar homeostatic processes; human homologs of two of them could be associated with as yet undefined disease states arising from aberrant metal ion regulation. The Met4, Met31, and Met32 transcription factors may play a role in coregulating genes involved in copper and iron metabolism. Extensions of the simple graphical model used for clustering to learning more complex models of genetic networks are discussed.

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