4.8 Article

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

Journal

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 24, Pages 9330-9334

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202000983

Keywords

enzymes; histone H2B; mitochondria; peptides; self-assembly

Funding

  1. NIH [R01CA142746]
  2. NSF [MRSEC-1420382]

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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.

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