Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy
Open accessAbstract
Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited. Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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Cuprizone-mediated reduction in oligodendrocytes between days 1-4 coincides with reduction of the iron storage protein ferritin and an increase of the ferroptosis marker NCOA4.
“Cuprizone-mediated reduction in oligodendrocytes between days 1–4 coincides with reduction of the iron storage protein ferritin and an increase of the ferroptosis marker nuclear receptor coactivator 4 (NCOA4).”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [287]
The Abstract identifies ferritin as an iron-storage protein and reports that NCOA4 promotes ferritin turnover; Extended Data Figure 10 also links NCOA4 levels to ferritin levels. The paper does not report cuprizone-treated oligodendrocytes, changes between days 1–4, or an increase in NCOA4 as a ferroptosis marker. Page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHydroxychloroquine enhances PDAC patient response to chemotherapy.
“clinical trials have shown that hydroxychloroquine, which inhibits autophagic flux by preventing lysosomal acidification, enhances PDAC patient response to chemotherapy212,213”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [213]
NCOA4 was identified as the cargo receptor for autophagocytotic turnover of ferritin.
“Recently, nuclear receptor coactivator 4 (NCOA4) was identified as the cargo receptor for autophagocytotic turnover of ferritin”
From Iron in immune cell function and host defense (2021) · cites this paper as [9]
Ferritinophagy is specifically mediated via NCOA4 to traffic ferritin to the autophagosome for degradation.
“This process is specifically mediated via NCOA4 to traffic ferritin to the autophagosome for degradation”
From Iron in immune cell function and host defense (2021) · cites this paper as [9]
In primary MEFs, Dfo (50 μM) stimulated ferritin degradation substantially within 6 h.
“Ferritin degradation was then stimulated with the iron chelator deferoxamine (Dfo) (50 µM) as previously described [51], [53], [56] and occurred substantially within 6 h of treatment (Fig. 5A(i)).”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [53]
Ferritinophagy is important for liberating iron from ferritin and for maintaining cellular iron homeostasis.
“Ferritinophagy, the process of ferritin being sequestered into autophagosomes and delivered to lysosomes for degradation, is important for liberating iron from ferritin and thus for maintaining cellular iron homeostasis [51], [53], [54], [55].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [53]
Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4, a process required for liberating iron making it bioavailable.
“Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4 [53], a process required for liberating iron making it bioavailable to the cell [51], [53], [65].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [53]
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- Authors
- Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W., & Kimmelman, A. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Corresponding author
- Harper, J. Wade
- Kimmelman, Alec C.
- Venue
- Nature
- Published
- 2014-03-30
- Volume
- 509
- Issue
- 7498
- Pages
- 105-109
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4180099
- OpenAlex
- W1996152690
- Cited by
- 2,084
- References
- 30
- Citations by year
- 2026: 289 · 2025: 335 · 2024: 311 · 2023: 292 · 2022: 212 · 2021: 192 · 2020: 110 · 2019: 96 · 2018: 64 · 2017: 69 · 2016: 57 · 2015: 36 · 2014: 19 · 2013: 1
- FWCI
- 45.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P50CA127003, R01CA157490)
- National Institute of General Medical Sciences (R01GM095567, R01GM070565, GM095567, GM070565)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- NCOA4, ferritinophagy, selective autophagy, cargo receptors, autophagosomes, iron homeostasis, iron starvation, ferritin degradation, ATG8, lysosomal degradation, iron metabolism, quantitative proteomics, lysosomal biogenesis
- MeSH terms
- Autophagy-Related Protein 8 Family, Autophagy, Biological Availability, Ferritins, Homeostasis, Humans, Iron, Lysosomes, Microfilament Proteins, Phagosomes, Protein Binding, Substrate Specificity, Protein Transport, Proteomics, Adaptor Proteins, Signal Transducing, Nuclear Receptor Coactivators
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