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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 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.

SUBMITTER: Chairatana P

PROVIDER: S-EPMC4827351 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.

Chairatana Phoom P Chu Hiutung H Castillo Patricia A PA Shen Bo B Bevins Charles L CL Nolan Elizabeth M EM

Chemical science 20151210 3

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 mat ...[more]

PMID: 27076903

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Project description:Human α-defensin 6 (HD6) is a 32-residue cysteine-rich peptide that contributes to innate immunity by protecting the host at mucosal sites. This peptide is produced in small intestinal Paneth cells, stored as an 81-residue precursor peptide named proHD6 in granules, and released into the lumen. One unusual feature of HD6 is that it lacks the broad-spectrum antimicrobial activity observed for other human α-defensins, including the Paneth cell peptide human α-defensin 5 (HD5). HD6 exhibits unprecedented self-assembly properties, which confer an unusual host-defense function. HD6 monomers self-assemble into higher-order oligomers termed "nanonets", which entrap microbes and prevent invasive gastrointestinal pathogens such as Salmonella enterica serovar Typhimurium and Listeria monocytogenes from entering host cells. One possible advantage of this host-defense mechanism is that HD6 helps to keep microbes in the lumen such that they can be excreted or attacked by other components of the immune system, such as recruited neutrophils. In this Account, we report our current understanding of HD6 and focus on work published since 2012 when Bevins and co-workers described the discovery of HD6 nanonets in the literature. First, we present studies that address the biosynthesis, storage, and maturation of HD6, which demonstrate that nature uses a propeptide strategy to spatially and temporally control the formation of HD6 nanonets in the small intestine. The propeptide is stored in Paneth cell granules, and proteolysis occurs during or following release into the lumen, which affords the 32-residue mature peptide that self-assembles. We subsequently highlight structure-function studies that provide a foundation for understanding the molecular basis for why HD6 exhibits unusual self-assembly properties compared with other characterized defensins. The disposition of hydrophobic residues in the HD6 primary structure differs from that of other human α-defensins and is an important structural determinant for oligomerization. Lastly, we consider functional studies that illuminate how HD6 contributes to mucosal immunity. We recently discovered that in addition to blocking bacterial invasion into host epithelial cells by Gram-negative and Gram-positive gastrointestinal pathogens, HD6 suppresses virulence traits displayed by the opportunistic human fungal pathogen Candida albicans. In particular, we found that C. albicans biofilm formation, which causes complications in the treatment of candidiasis, is inhibited by HD6. This observation suggests that HD6 may contribute to intestinal homeostasis by helping to keep C. albicans in its commensal state. We intend for this Account to inspire further biochemical, biophysical, and biological investigations that will advance our understanding of HD6 in mucosal immunity and the host-microbe interaction.

Dataset Information

Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.

Publications

Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.

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