Publication Date:
2014-04-04
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180099/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180099/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mancias, Joseph D -- Wang, Xiaoxu -- Gygi, Steven P -- Harper, J Wade -- Kimmelman, Alec C -- GM070565/GM/NIGMS NIH HHS/ -- GM095567/GM/NIGMS NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- R01 CA157490/CA/NCI NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- R01CA157490/CA/NCI NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):105-9. doi: 10.1038/nature13148. Epub 2014 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Radiation Oncology Program, Boston, Massachusetts 02115, USA [4] Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695223" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing/metabolism
;
*Autophagy
;
Biological Availability
;
Ferritins/chemistry/*metabolism
;
Homeostasis
;
Humans
;
Iron/metabolism
;
Lysosomes/metabolism
;
Microfilament Proteins/metabolism
;
Nuclear Receptor Coactivators/deficiency/genetics/*metabolism
;
Phagosomes/*metabolism
;
Protein Binding
;
Protein Transport
;
*Proteomics
;
Substrate Specificity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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