The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity.
OTUD1
colorectal cancer
ferroptosis
iron transportation
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
03 02 2021
03 02 2021
Historique:
received:
23
06
2020
revised:
02
12
2020
accepted:
03
12
2020
pubmed:
5
1
2021
medline:
1
6
2021
entrez:
4
1
2021
Statut:
ppublish
Résumé
Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.
Identifiants
pubmed: 33393230
doi: 10.15252/embr.202051162
pmc: PMC7857436
doi:
Substances chimiques
Antigens, CD
0
CD71 antigen
0
Receptors, Transferrin
0
Iron
E1UOL152H7
OTUD1 protein, human
EC 3.4.19.12
Ubiquitin-Specific Proteases
EC 3.4.19.12
IREB2 protein, human
EC 4.2.1.3
Iron Regulatory Protein 2
EC 4.2.1.3
Banques de données
GEO
['GSE140059']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e51162Informations de copyright
© 2021 The Authors.
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