NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis

Zhao, Hongting; Lu, Yao; Zhang, Jinghua; Sun, Zichen; Cheng, Chen; Liu, Yutong; Wu, Lin; Zhang, Meng; He, Weijiang; Hao, Shuangying; Li, Kuanyu

doi:10.1016/j.jbc.2023.105612

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…Given that the NCOA4•GATE16 interaction is crucial in the progression of ferritinophagy, an iron sensing pathway, we next asked whether iron could regulate this interaction. It was recently reported that NCOA4 383−522 can bind an iron-sulfur cluster coordinated by four cysteines ( Zhao et al, 2024 ). Importantly, one of these four cysteines, residue 416, is present in the 413 FAECV 417 LIR-like motif we have described.…”

Section: Resultsmentioning

confidence: 99%

“…As the process of ferritinophagy releases iron predominantly in response to iron depletion, there are several proposed mechanisms linking ferritinophagy to levels of labile iron. In one model, in iron replete conditions, the E3 ubiquitin ligase HERC2 binds to NCOA4 and promotes its degradation via the proteasome ( Mancias et al, 2015 ; Zhao et al, 2024 ), thereby negatively regulating ferritinophagy. Additionally, Zhao et al recently showed that NCOA4 binds an iron-sulfur cluster, which is coordinated using cysteine residues 404, 410, 416 and 422, and that ablation of the iron-sulfur cluster increases NCOA4’s affinity for ferritin ( Zhao et al, 2024 ).…”

Section: Discussionmentioning

confidence: 99%

“…In one model, in iron replete conditions, the E3 ubiquitin ligase HERC2 binds to NCOA4 and promotes its degradation via the proteasome ( Mancias et al, 2015 ; Zhao et al, 2024 ), thereby negatively regulating ferritinophagy. Additionally, Zhao et al recently showed that NCOA4 binds an iron-sulfur cluster, which is coordinated using cysteine residues 404, 410, 416 and 422, and that ablation of the iron-sulfur cluster increases NCOA4’s affinity for ferritin ( Zhao et al, 2024 ). Interestingly, cysteine 416 is contained in our described GATE16-binding 413 FAECV 417 motif, raising the possibility of iron-sulfur dependent regulation of this binding activity.…”

Section: Discussionmentioning

confidence: 99%

“…Ferritinophagy is thought to rely on the protein Nuclear Receptor Coactivator 4 (NCOA4), which was first identified as a selective autophagy receptor in an LC-MS/MS based proteomics approach targeting proteins that copurified with autophagosomes ( Mancias et al, 2014 ). The activity of NCOA4 is regulated via iron-dependent ( Zhao et al, 2024 ) changes in affinity for ferritin as well as an E3 ligase HERC2, which can promote NCOA4 degradation via the proteasome ( Mancias et al, 2015 ). An NCOA4 fragment composed of residues 383–522 (NCOA4 383−522 , hereafter) was subsequently found to be sufficient to bind directly to ferritin and to interact with proteins in the autophagic machinery ( Hoelzgen et al, 2024 ; Mancias et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs

Lee,

Davis

2024

Preprint

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Cells carefully regulate cytosolic iron, which is a vital enzymatic cofactor, yet is toxic in excess. In mammalian cells, surplus iron is sequestered in ferritin cages that, in iron limiting conditions, are degraded through the selective autophagy pathway ferritinophagy to liberate free iron. Prior work identified the ferritinophagy receptor protein NCOA4, which links ferritin and LC3/GABARAP-family member GATE16, effectively tethering ferritin to the autophagic machinery. Here, we elucidate the molecular mechanism underlying this interaction, discovering two short linear motifs in NCOA4 that each bind GATE16 with weak affinity. These binding motifs are highly avid and, in concert, support high-affinity NCOA4•GATE16 complex formation. We further find the minimal NCOA4383-522fragment bearing these motifs is sufficient for ferritinophagy and that both motifs are necessary for this activity. This work suggests a general mechanism wherein selective autophagy receptors can distinguish between the inactive soluble pools of LC3/GABARAPs and the active membrane-conjugated forms that drive autophagy. Finally, we find that iron decreases NCOA4383-522’s affinity for GATE16, providing a plausible mechanism for iron-dependent regulation of ferritinophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs

Lee,

Davis

2024

Preprint

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“…NCOA4 was known to bind iron and regulate ferritinophagy in response to iron levels, but until recently it was unknown how NCOA4 sensed iron [28,177]. NCOA4 has now been proposed as both an oxygen sensor [180] and an intracellular iron sensor [181] due to its ligation of an Fe-S cluster. These new discoveries highlight the inextricable link between Fe-S clusters and the regulation of intracellular regulation of iron metabolism.…”

Section: Mammalian Iron-sensing Iron-sulfur Clustersmentioning

confidence: 99%

Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions

SantaMaria,

Rouault

2024

Inorganics

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Iron is an essential nutrient and necessary for biological functions from DNA replication and repair to transcriptional regulation, mitochondrial respiration, electron transfer, oxygen transport, photosynthesis, enzymatic catalysis, and nitrogen fixation. However, due to iron’s propensity to generate toxic radicals which can cause damage to DNA, proteins, and lipids, multiple processes regulate the uptake and distribution of iron in living systems. Understanding how intracellular iron metabolism is optimized and how iron is utilized to regulate other intracellular processes is important to our overall understanding of a multitude of biological processes. One of the tools that the cell utilizes to regulate a multitude of functions is the ligation of the iron–sulfur (Fe-S) cluster cofactor. Fe-S clusters comprised of iron and inorganic sulfur are ancient components of living matter on earth that are integral for physiological function in all domains of life. FeS clusters that function as biological sensors have been implicated in a diverse group of life from mammals to bacteria, fungi, plants, and archaea. Here, we will explore the ways in which cells and organisms utilize Fe-S clusters to sense changes in their intracellular environment and restore equilibrium.

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Unveiling the stochastic nature of human heteropolymer ferritin self‐assembly mechanism

Bou‐Abdallah,

Fish,

Terashi

et al. 2024

Protein Science

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Despite ferritin's critical role in regulating cellular and systemic iron levels, our understanding of the structure and assembly mechanism of isoferritins, discovered over eight decades ago, remains limited. Unveiling how the composition and molecular architecture of hetero‐oligomeric ferritins confer distinct functionality to isoferritins is essential to understanding how the structural intricacies of H and L subunits influence their interactions with cellular machinery. In this study, ferritin heteropolymers with specific H to L subunit ratios were synthesized using a uniquely engineered plasmid design, followed by high‐resolution cryo‐electron microscopy analysis and deep learning‐based amino acid modeling. Our structural examination revealed unique architectural features during the self‐assembly mechanism of heteropolymer ferritins and demonstrated a significant preference for H‐L heterodimer formation over H‐H or L‐L homodimers. Unexpectedly, while dimers seem essential building blocks in the protein self‐assembly process, the overall mechanism of ferritin self‐assembly is observed to proceed randomly through diverse pathways. The physiological significance of these findings is discussed including how ferritin microheterogeneity could represent a tissue‐specific adaptation process that imparts distinctive tissue‐specific functions to isoferritins.

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NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis

Cited by 8 publications

References 40 publications

NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs

NCOA4 initiates ferritinophagy by binding GATE16 using two highly avid short linear interaction motifs

Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions

Unveiling the stochastic nature of human heteropolymer ferritin self‐assembly mechanism

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