<p>It is known that a
highly dynamic communication among subcellular organelles (e.g., cytosol,
endoplasmic reticulum (ER), mitochondria, and nucleus) dictate cellular
behaviors. But little information exists on how the inter-organelle crosstalk
impacts cancer cells due to the lack of approaches that manipulate
inter-organelle communication in cancer cells. We unexpectedly found that a negatively
charged, enzyme cleavable peptide enables the trafficking of histone protein
(H2B), a nuclear protein, to the mitochondria in cancer cells. The peptide,
denoted as MitoFlag, interacts with the nuclear location sequence (NLS) of H2B
to block it entering nucleus. A protease on the mitochondria cleaves the Flag
from the complex of MitoFlag and H2B to form assemblies that retain H2B on the
mitochondria and facilitate the H2B entering mitochondria. Molecular validation
of MitoFlag shows that adding NLS, replacing aspartic acid residues by glutamic
acid residues, or changing L-aspartic acid to D-aspartic residue abolishes the
trafficking of H2B into mitochondria of HeLa cells. As the first example of
enzyme-instructed self-assembly (EISA) of a synthetic peptide for trafficking endogenous
proteins, this work provides insights for understanding and manipulating
inter-organelle communication in cells.</p>
An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β