UBE2N inhibition is sufficient to attenuate TIFAsome signaling in leukemic cells
2023
Online
Hochschulschrift
Acute Myeloid Leukemia (AML) represents an ever-changing disease that is difficult to treat due to the ability of cancer cells to adapt to therapies and utilize multiple pathways to survive. AML often co-occurs with other immune and inflammatory disorders suggesting a common link. Emerging data have revealed that microbial metabolites from a dysregulated gut microbiome may contribute to AML development. One such metabolite, ADPheptose, has been recently identified and its systemic circulation is associated with the expansion of leukemic cells. Despite the link between ADPheptose and leukemic cells, the mechanisms by how ADPheptose contributes to the leukemic cell phenotypes remain unknown. This study reveals the effects of ADPheptose on AML patient samples and leukemic cell lines. Specifically, ADPheptose activates canonical NF-kB signaling upon formation of a multimeric protein complex referred to as the TIFAsome. Moreover, ADPheptose-mediated activation of NF-kB via TIFAsomes does not utilize the conventional effectors of NF-kB. Instead, ADPheptose-mediated activation of NF-kB requires the E2 conjugating enzyme UBE2N and the E3 ubiquitin ligase TRAF6. Finally, we shown that circulating ADPhepotse from aged and MDS plasma, but not healthy young plasma, is sufficient to initiate TIFAsome assembly and activate NF-kB signaling in leukemic cells. This study reveals the molecular basis for how an age-associated bacterial metabolite can contribute to the expansion of leukemic cells and contribute to AML development.
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UBE2N inhibition is sufficient to attenuate TIFAsome signaling in leukemic cells
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Autor/in / Beteiligte Person: | Sampson, Avery |
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Veröffentlichung: | 2023 |
Medientyp: | Hochschulschrift |
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