title: Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.
abstract: Human α-defensin 6 (HD6) is a unique peptide of the defensin family that provides innate immunity in the intestine by self-assembling to form high-order oligomers that entrap bacteria and prevent host cell invasion. Here, we report critical steps in the self-assembly pathway of HD6. We demonstrate that HD6 is localized in secretory granules of small intestinal Paneth cells. HD6 is stored in these granules as an 81-residue propeptide (proHD6), and is recovered from ileal lumen as a 32-residue mature peptide. The propeptide neither forms higher-order oligomers, nor agglutinates bacteria, nor preventsListeria monocytogenesinvasion into epithelial cells. The Paneth cell granules also contain the protease trypsin, and trypsin-catalyzed hydrolysis of proHD6 liberates mature HD6, unmasking its latent activities. This work illustrates a remarkable example of how nature utilizes a propeptide strategy to spatially and temporally control peptide self-assembly, and thereby initiates innate immune function in the human intestine.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Phoom
authors.initials: P
authors.lastname: Chairatana
authors.affiliation: Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Hiutung
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Castillo
authors.affiliation: Department of General Internal Medicine and Gastroenterology and Hepatology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bevins
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Nolan