Figure 9.

Two pathways of nuclear import and their inhibition by a bifunctional NTM. A, Nuclear translocation of transcription factors that bear a basic bHLH‐Zip motif (bHLH), such as the SREBP proteins, is mediated by binding of their bHLH region directly to importin beta (Imp β, left). Consequently, multiple genes that encode proteins involved in cholesterol, triglyceride, and fatty acid synthesis are activated. Transcription factors containing a classic NLS motif, such as NFκB, are ferried by binding of their NLS region to importin alpha (Imp α, right), which then forms a complex with importin beta for nuclear translocation to activate a myriad of genes that encode mediators of inflammation and immunity. B, In cells treated with NTM peptide, the SSHR‐2 domain of the peptide occupies the bHLH‐Zip docking site on importin beta (left), whereas the NLS domain occupies the NLS‐binding pocket on importin alpha (right), preventing transcription factor attachment and subsequent nuclear translocation and gene transcription. NTM indicates nuclear transport modifier; SREBP, sterol regulatory element‐binding protein; NLS, nuclear localization sequence; SSHR, signal sequence hydrophobic region.