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Biology subjects

Graff, P.

Publications and source records attributed to Graff, P..

2 recordsLinked to original sources

Divergent TLR2 and TLR4 activation by fungal spores and species diversity in dust from waste-sorting plants

1.This manuscript presents the results of an exploratory study on the relationships between NFkB (Nuclear Factor Kappa Chain Enhancer of B-cells) response through TLRs activation by dust characterized by fungal spore concentrations and species diversity. Personal total dust samples were collected from Norwegian waste sorting plants and then characterized for fungal spores and fungal species diversity, as well as for other bioaerosol components, including endotoxins and actinobacteria. The ability of the dust to induce an NFkB response by activating Toll-like receptors 2 (TLR2) and 4 (TLR4) in vitro was evaluated as well as the relationship between such responses and quantifiable bioaerosol components. The average concentrations of bioaerosols were 7.23 mg total dust m-3, 4.49x105 fungal spores m-3, 814 endotoxin units m-3, and 0.6x105 actinobacteria m-3. The mean diversity measurements were 326; 0.59 and 3.39 for fungal richness, evenness, and Shannon Index, respectively. Overall, fungal OTUs belonging to the Ascomycotina phylum were most abundant (55%), followed by Basidiomycota (33%) and Mucormycota (3%). All samples induced significant NFkB responses through TLR2 and TLR4 activation. While fungal spore levels were positively associated with TLR2 and TLR4 activation, there was a trend that fungal species richness was negatively associated with the activation of these receptors. This observation supports the existence of divergent immunological responses relationship between fungal spore levels and fungal species diversity. Such relationships seem to be described for the first time for dust from waste facilities.

microbiology↗

The Structural Basis of Indisulam-Mediated Recruitment of RBM39 to the DCAF15-DDB1-DDA1 E3 Ligase Complex

The anti-cancer agent Indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which Indisulam mediates DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-Indisulam-RBM39(RRM2) complex structure to 2.3 [A]. DCAF15 has a novel topology which embraces the RBM39(RRM2) domain largely via nonpolar interactions, and Indisulam binds between DCAF15 and RBM39(RRM2) and coordinates additional interactions between the two proteins. Studies with RBM39 point mutants and Indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39 and only these proteins were detectably downregulated in Indisulam-treated HCT116 cells. This work further explains how Indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade novel targets.

biophysics↗