Browsing by Subject "HIF-1α"

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    Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.
    (Eur J Immunol, 2016-08) Gerriets, Valerie A; Danzaki, Keiko; Kishton, Rigel J; Eisner, William; Nichols, Amanda G; Saucillo, Donte C; Shinohara, Mari L; MacIver, Nancie J
    Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but not Treg-cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff-cell glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.
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    Regulation of HIF-1α during Hypoxia by DAP5-Induced Translation of PHD2
    (2018) Bryant, Jeffrey

    Death associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffold eukaryotic initiation factors 4GI and II (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. Despite extensive work describing eIF4GI, an understanding of DAP5 activation is yet to be described.

    Here I describe our discovery that DAP5:eIF2β binding is regulated by DAP5 phosphorylation and can be stimulated by specific stimuli including protein kinase C PKC-Raf-ERK1/2 signals, mitosis and hypoxia, wherein DAP5:eIF2β binding determines DAP5’s influence on global and template-specific translation. However, DAP5 depletion causes an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. The hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2), and subsequent ubiquitination and degradation. Furthermore, we found that DAP5 regulates HIF-1α abundance and Akt signaling through DAP5:eIF2β-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurs during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response implying that DAP5:eIF2β binding may describe a conserved mechanism for selective stress induced translation.