A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
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Authors
Saveljeva, Svetlana
Sewell, Gavin W
Ramshorn, Katharina
Cader, M Zaeem
West, James A
Clare, Simon
Haag, Lea-Maxie
de Almeida Rodrigues, Rodrigo Pereira
Unger, Lukas W
Iglesias-Romero, Ana Belén
Holland, Lorraine M
Bourges, Christophe
Md-Ibrahim, Muhammad N
Jones, James O
Blumberg, Richard S
Lee, James C
Kaneider, Nicole C
Lawley, Trevor D
Kaser, Arthur
Publication Date
2022-01-04Journal Title
Cell Metab
ISSN
1550-4131
Publisher
Elsevier BV
Volume
34
Issue
1
Pages
106-124.e10
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Saveljeva, S., Sewell, G. W., Ramshorn, K., Cader, M. Z., West, J. A., Clare, S., Haag, L., et al. (2022). A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.. Cell Metab, 34 (1), 106-124.e10. https://doi.org/10.1016/j.cmet.2021.12.009
Abstract
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
Keywords
Dendritic cells, Autoimmunity, membrane trafficking, T Cell Priming, Purine Nucleotide Cycle, Nadh/nad(+) Reductive Stress
Sponsorship
European Research Council (260961)
Wellcome Trust (103077/Z/13/Z)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
Academy of Medical Sciences (AOMS-)
Wellcome Trust (105920/Z/14/Z)
Wellcome Trust (102163/B/13/Z)
Wellcome Trust (216630/Z/19/Z)
MRC (MC_UU_00014/5)
Identifiers
34986329, PMC8730334
External DOI: https://doi.org/10.1016/j.cmet.2021.12.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333690
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