Global Analysis of Intercellular Homeodomain Protein Transfer
Eun Jung Lee,
Namsuk Kim,
Jun Woo Park,
Kyung Hwa Kang,
Woo-il Kim,
Nam Suk Sim,
Chan-Seok Jeong,
Seth Blackshaw,
Marc Vidal,
Sung-Oh Huh,
Dongsup Kim,
Jeong Ho Lee,
Jin Woo Kim
Affiliations
Eun Jung Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Namsuk Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Jun Woo Park
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Kyung Hwa Kang
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; KAIST Institute of BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Woo-il Kim
Graduate School of Biomedical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Nam Suk Sim
Graduate School of Biomedical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Chan-Seok Jeong
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Seth Blackshaw
Department of Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Marc Vidal
Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Sung-Oh Huh
Department of Pharmacology, Chuncheon Translational Research Center, College of Medicine, Hallym University, Chuncheon 24252, South Korea
Dongsup Kim
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Jeong Ho Lee
KAIST Institute of BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Graduate School of Biomedical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
Jin Woo Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; KAIST Institute of BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Corresponding author
Summary: The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (HPs) are thought to be secreted and penetrate neighboring cells to affect the recipient cell fate. To determine whether this is a general characteristic of HPs, we carried out a large-scale validation for intercellular transfer of HPs. Our screening reveals that intercellular transfer is a general feature of HPs, but it occurs in a cell-context-sensitive manner. We also found the secretion is not solely a function of the homeodomain, but it is supported by external motifs containing hydrophobic residues. Thus, mutations of hydrophobic residues of HPs abrogate secretion and consequently interfere with HP function in recipient cells. Collectively, our study proposes that HP transfer is an intercellular communication method that couples the functions of interacting cells. : Lee et al. evaluate capabilities of homeodomain proteins (HPs) for transfer between cells. They find that intercellular transfer is a general but cell-context-sensitive property of HP. Intercellular HP transfer can be an unconventional way for the cells to communicate with neighboring cells that associate structurally and functionally. Keywords: homeodomain, cell-penetrating protein, protein secretion, intercellular protein transfer