Reawakening retrocyclins: ancestral human defensins active against HIV-1.

Human alpha and beta defensins contribute substantially to innate immune defenses against microbial and viral infections. Certain nonhuman primates also produce theta-defensins-18 residue cyclic peptides that act as HIV-1 entry inhibitors. Multiple human theta-defensin genes exist, but they harbor a...

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Autores principales:	Nitya Venkataraman, Amy L Cole, Piotr Ruchala, Alan J Waring, Robert I Lehrer, Olga Stuchlik, Jan Pohl, Alexander M Cole
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f8b480c4c8ed42c79bbeceed7bb3ce6f
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spelling	oai:doaj.org-article:f8b480c4c8ed42c79bbeceed7bb3ce6f2021-11-25T05:34:12ZReawakening retrocyclins: ancestral human defensins active against HIV-1.1544-91731545-788510.1371/journal.pbio.1000095https://doaj.org/article/f8b480c4c8ed42c79bbeceed7bb3ce6f2009-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19402752/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Human alpha and beta defensins contribute substantially to innate immune defenses against microbial and viral infections. Certain nonhuman primates also produce theta-defensins-18 residue cyclic peptides that act as HIV-1 entry inhibitors. Multiple human theta-defensin genes exist, but they harbor a premature termination codon that blocks translation. Consequently, the theta-defensins (retrocyclins) encoded within the human genome are not expressed as peptides. In vivo production of theta-defensins in rhesus macaques involves the post-translational ligation of two nonapeptides, each derived from a 12-residue "demidefensin" precursor. Neither the mechanism of this unique process nor its existence in human cells is known. To ascertain if human cells retained the ability to process demidefensins, we transfected human promyelocytic cells with plasmids containing repaired retrocyclin-like genes. The expected peptides were isolated, their sequences were verified by mass spectrometric analyses, and their anti-HIV-1 activity was confirmed in vitro. Our study reveals for the first time, to our knowledge, that human cells have the ability to make cyclic theta-defensins. Given this evidence that human cells could make theta-defensins, we attempted to restore endogenous expression of retrocyclin peptides. Since human theta-defensin genes are transcribed, we used aminoglycosides to read-through the premature termination codon found in the mRNA transcripts. This treatment induced the production of intact, bioactive retrocyclin-1 peptide by human epithelial cells and cervicovaginal tissues. The ability to reawaken retrocyclin genes from their 7 million years of slumber using aminoglycosides could provide a novel way to secure enhanced resistance to HIV-1 infection.Nitya VenkataramanAmy L ColePiotr RuchalaAlan J WaringRobert I LehrerOlga StuchlikJan PohlAlexander M ColePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 4, p e95 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Nitya Venkataraman Amy L Cole Piotr Ruchala Alan J Waring Robert I Lehrer Olga Stuchlik Jan Pohl Alexander M Cole Reawakening retrocyclins: ancestral human defensins active against HIV-1.
description	Human alpha and beta defensins contribute substantially to innate immune defenses against microbial and viral infections. Certain nonhuman primates also produce theta-defensins-18 residue cyclic peptides that act as HIV-1 entry inhibitors. Multiple human theta-defensin genes exist, but they harbor a premature termination codon that blocks translation. Consequently, the theta-defensins (retrocyclins) encoded within the human genome are not expressed as peptides. In vivo production of theta-defensins in rhesus macaques involves the post-translational ligation of two nonapeptides, each derived from a 12-residue "demidefensin" precursor. Neither the mechanism of this unique process nor its existence in human cells is known. To ascertain if human cells retained the ability to process demidefensins, we transfected human promyelocytic cells with plasmids containing repaired retrocyclin-like genes. The expected peptides were isolated, their sequences were verified by mass spectrometric analyses, and their anti-HIV-1 activity was confirmed in vitro. Our study reveals for the first time, to our knowledge, that human cells have the ability to make cyclic theta-defensins. Given this evidence that human cells could make theta-defensins, we attempted to restore endogenous expression of retrocyclin peptides. Since human theta-defensin genes are transcribed, we used aminoglycosides to read-through the premature termination codon found in the mRNA transcripts. This treatment induced the production of intact, bioactive retrocyclin-1 peptide by human epithelial cells and cervicovaginal tissues. The ability to reawaken retrocyclin genes from their 7 million years of slumber using aminoglycosides could provide a novel way to secure enhanced resistance to HIV-1 infection.
format	article
author	Nitya Venkataraman Amy L Cole Piotr Ruchala Alan J Waring Robert I Lehrer Olga Stuchlik Jan Pohl Alexander M Cole
author_facet	Nitya Venkataraman Amy L Cole Piotr Ruchala Alan J Waring Robert I Lehrer Olga Stuchlik Jan Pohl Alexander M Cole
author_sort	Nitya Venkataraman
title	Reawakening retrocyclins: ancestral human defensins active against HIV-1.
title_short	Reawakening retrocyclins: ancestral human defensins active against HIV-1.
title_full	Reawakening retrocyclins: ancestral human defensins active against HIV-1.
title_fullStr	Reawakening retrocyclins: ancestral human defensins active against HIV-1.
title_full_unstemmed	Reawakening retrocyclins: ancestral human defensins active against HIV-1.
title_sort	reawakening retrocyclins: ancestral human defensins active against hiv-1.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/f8b480c4c8ed42c79bbeceed7bb3ce6f
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Reawakening retrocyclins: ancestral human defensins active against HIV-1.

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