Proteolysis triggers self-assembly and unmasks innate immune function of a human α-defensin peptide

Phoom Chairatana, Hiutung Chu, Patricia A. Castillo, Bo Shen, Charles L Bevins, Elizabeth M. Nolan

Research output: Contribution to journalArticle

12 Scopus citations

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 higher-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 prevents Listeria monocytogenes invasion 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.

Original languageEnglish (US)
Pages (from-to)1738-1752
Number of pages15
JournalChemical Science
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)

Cite this