Enzyme‐Instructed Assemblies Enable Mitochondria Localization of Histone H2B in Cancer Cells

Abstract

Presently, little is known of how the inter‐organelle crosstalk impacts cancer cells owing to the lack of approaches that can manipulate inter‐organelle communication in cancer cells. We found that a negatively charged, enzyme cleavable peptide (MitoFlag) enables the trafficking of histone protein H2B, a nuclear protein, to the mitochondria in cancer cells. MitoFlag interacts with the nuclear location sequence of H2B to block it from entering the nucleus. A protease on the mitochondria cleaves the Flag from the MitoFlag/H2B complex to form assemblies that retain H2B on the mitochondria and facilitate H2B entering the mitochondria. Adding NLS, replacing aspartic acid by glutamic acid residues, or changing the l‐ to d‐aspartic acid residue on MitoFlag abolishes the trafficking of H2B into mitochondria of HeLa cells. As the first example of the enzyme‐instructed self‐assembly of a synthetic peptide for trafficking endogenous proteins, this work provides insights for understanding and manipulating inter‐organelle communication in cells.

Structure‐Based Programming of Supramolecular Assemblies in Living Cells for Selective Cancer Cell Inhibition

“…The stability represents an important characteristic for the activity of EISA precursor. However, the systematic study of the stability of precursor in serum has yet to be explored in using EISA to kill cancer cells [1b,c, 4c] . The serum contains a wide variety of proteinases and peptidases, affecting the final anti‐cancer cell efficacy of self‐assembling peptides.…”

Biological functions of supramolecular assemblies of small molecules in the cellular environment

“…In addition, the cytotoxicity of a combination of 15 and Dox to cancer cells is higher than that of Dox alone. 62 This method underscores the use of SASMs for manipulating inter-organelle crosstalk, which remains underexplored. In addition, this method should be applicable to combine other clinical drugs with SASMs for inhibiting cancer cells effectively.…”

Evolution of Supramolecular Systems Towards Next-Generation Biosensors

“…Nonetheless, the examples of supramolecular materials used for differentially screening or identifying cells (e.g., tumorigenic vs. healthy) and bacteria highlighted in earlier sections suggest that the field is now significantly past establishing the proof-ofprinciple for detecting these analytes. Recent studies that explore the supramolecular assembly dynamics within cellular environments or sub-cellular localization present the future potential of having more controlled detection schemes within the biological millieu (Krivitsky et al, 2019;Bai et al, 2020;He et al, 2020;Pieszka et al, 2020).…”