The TRIpartite Motif (TRIM) family of RING-domain-containing proteins participate in a variety of cellular functions. The β-transducin repeat-containing protein (β-TrCP), a component of the Skp-Cullin-F-box-containing (SCF) E3 ubiquitin ligase complex, recognizes the NF-κB inhibitor IκBα and precursor p100 for proteasomal degradation and processing respectively. β-TrCP thus plays a critical role in both canonical and non-canonical NF-κB activation. Here, we report TRIM9 is a negative regulator of NF-κBactivation. Interaction between the phosphorylated degron motif of TRIM9 and the WD40 repeat region of β-TrCP prevented β-TrCP from binding its substrates, stabilizing IκBα and p100 and thereby blocking NF-κB activation. Consequently, expression or depletion of the TRIM9 gene significantly affected NF-κB-induced inflammatory cytokine production. This study not only elucidates a mechanism for TRIM9-mediated regulation of the β-TrCP SCF complex activity, but also identifies TRIM9 as a brain-specific negative regulator of the NF-κB pro-inflammatory signaling pathway.

Methuosis is a form of nonapoptotic cell death characterized by the accumulation of macropinosome-derived vacuoles. Herein, we identify PIKFYVE, a class III phosphoinositide (PI) kinase, as the protein target responsible for the methuosis-inducing activity of indolyl-pyridinyl-propenones (3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one). We further characterize the effects of chemical substitutions at the 2- and 5-indolyl positions on cytoplasmic vacuolization and PIKFYVE binding and inhibitory activity. Our study provides a better understanding of the mechanism of methuosis-inducing indolyl-pyridinyl-propenones.

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