| RRC ID |
15308
|
| 著者 |
Hara T, Mimura K, Abe T, Shioi G, Seiki M, Sakamoto T.
|
| タイトル |
Deletion of the Mint3/Apba3 gene in mice abrogates macrophage functions and increases resistance to lipopolysaccharide-induced septic shock.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Two major metabolic systems are usually used to generate ATP: oxidative phosphorylation (OXPHOS) in the mitochondria and glycolysis. Most types of cells employ OXPHOS for ATP production during normoxia but then shift energy production from OXPHOS to glycolysis when exposed to hypoxia. Hypoxia-inducible factor-1 (HIF-1) is the master transcription factor regulating this metabolic shift. On the other hand, macrophages are unique in making use of glycolysis for ATP generation constitutively even during normoxia. We recently proposed that in macrophages, Mint3/APBA3 inhibits factor inhibiting HIF-1 (FIH-1) during normoxia, which in turn releases the suppression of HIF-1 activity by FIH-1. To demonstrate the physiological function of APBA3 in macrophages, we established Apba3(-/-) mice. The mutant mice presented no apparent gross phenotype but exhibited significant resistance against LPS-induced septic shock. The level of ATP in macrophages obtained from the mutant mice was reduced to 60% of the level observed in wild type cells, which in turn led to reduced ATP-dependent activities such as glycolysis, cytokine production, and motility. We also generated mutant mice with the Apba3 gene deleted specifically from cells of the myeloid lineage and confirmed that LPS-induced septic shock is mitigated significantly. Thus, we show cell type-specific regulation of energy production by APBA3 in macrophages using genetically manipulated mice. The specific function of APBA3 in macrophages might allow us to develop therapeutics to regulate aberrant macrophage function during infection and diseases.
|
| 巻・号 |
286(37)
|
| ページ |
32542-51
|
| 公開日 |
2011-9-16
|
| DOI |
10.1074/jbc.M111.271726
|
| PII |
S0021-9258(20)50964-2
|
| PMID |
21778228
|
| PMC |
PMC3173149
|
| MeSH |
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cells, Cultured
Drug Resistance / drug effects
Drug Resistance / genetics
Energy Metabolism / drug effects*
Energy Metabolism / genetics
Gene Deletion
Hypoxia-Inducible Factor 1 / metabolism
Lipopolysaccharides / toxicity*
Macrophages / metabolism*
Macrophages / pathology
Mice
Mice, Knockout
Shock, Septic / chemically induced
Shock, Septic / genetics
Shock, Septic / metabolism*
Shock, Septic / pathology
|
| IF |
4.238
|
| 引用数 |
18
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC01834 |
