A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins
Abstract Background A considerable portion of the human genome derives from retroviruses inherited over millions of years. Human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERVs exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that...
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doaj-81513dc2430747268cbb6801fad48c082020-11-25T03:44:40ZengBMCMobile DNA1759-87532019-08-0110112210.1186/s13100-019-0178-zA human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteinsGiuseppe Rigogliuso0Martin L. Biniossek1John L. Goodier2Bettina Mayer3Gavin C. Pereira4Oliver Schilling5Eckart Meese6Jens Mayer7Department of Human Genetics, Medical Faculty, University of SaarlandInstitute of Molecular Medicine and Cell Research, University of FreiburgMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineInstitute of Molecular Medicine and Cell Research, University of FreiburgMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineInstitute of Surgical Pathology, Medical Center, University of FreiburgDepartment of Human Genetics, Medical Faculty, University of SaarlandDepartment of Human Genetics, Medical Faculty, University of SaarlandAbstract Background A considerable portion of the human genome derives from retroviruses inherited over millions of years. Human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERVs exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that encode typical retroviral proteins. HERV-K(HML-2) has been implicated in various human diseases because transcription is often upregulated and some of its encoded proteins are known to affect cell biology. HERV-K(HML-2) Protease (Pro) has received little attention so far, although it is expressed in some disease contexts and other retroviral proteases are known to process cellular proteins. Results We set out to identify human cellular proteins that are substrates of HERV-K(HML-2) Pro employing a modified Terminal Amine Isotopic Labeling of Substrates (TAILS) procedure. Thousands of human proteins were identified by this assay as significantly processed by HERV-K(HML-2) Pro at both acidic and neutral pH. We confirmed cleavage of a majority of selected human proteins in vitro and in co-expression experiments in vivo. Sizes of processing products observed for some of the tested proteins coincided with product sizes predicted by TAILS. Processed proteins locate to various cellular compartments and participate in diverse, often disease-relevant cellular processes. A limited number of HERV-K(HML-2) reference and non-reference loci appears capable of encoding active Pro. Conclusions Our findings from an approach combining TAILS with experimental verification of candidate proteins in vitro and in cultured cells suggest that hundreds of cellular proteins are potential substrates of HERV-K(HML-2) Pro. It is therefore conceivable that even low-level expression of HERV-K(HML-2) Pro affects levels of a diverse array of proteins and thus has a functional impact on cell biology and possible relevance for human diseases. Further studies are indicated to elucidate effects of HERV-K(HML-2) Pro expression regarding human substrate proteins, cell biology, and disease. The latter also calls for studies on expression of specific HERV-K(HML-2) loci capable of encoding active Pro. Endogenous retrovirus-encoded Pro activity may also be relevant for disease development in species other than human.http://link.springer.com/article/10.1186/s13100-019-0178-zHERV-KEndogenous retrovirusRetroviral proteaseProteolysisPathogenesisRetrotransposon |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giuseppe Rigogliuso Martin L. Biniossek John L. Goodier Bettina Mayer Gavin C. Pereira Oliver Schilling Eckart Meese Jens Mayer |
spellingShingle |
Giuseppe Rigogliuso Martin L. Biniossek John L. Goodier Bettina Mayer Gavin C. Pereira Oliver Schilling Eckart Meese Jens Mayer A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins Mobile DNA HERV-K Endogenous retrovirus Retroviral protease Proteolysis Pathogenesis Retrotransposon |
author_facet |
Giuseppe Rigogliuso Martin L. Biniossek John L. Goodier Bettina Mayer Gavin C. Pereira Oliver Schilling Eckart Meese Jens Mayer |
author_sort |
Giuseppe Rigogliuso |
title |
A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
title_short |
A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
title_full |
A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
title_fullStr |
A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
title_full_unstemmed |
A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
title_sort |
human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins |
publisher |
BMC |
series |
Mobile DNA |
issn |
1759-8753 |
publishDate |
2019-08-01 |
description |
Abstract Background A considerable portion of the human genome derives from retroviruses inherited over millions of years. Human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERVs exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that encode typical retroviral proteins. HERV-K(HML-2) has been implicated in various human diseases because transcription is often upregulated and some of its encoded proteins are known to affect cell biology. HERV-K(HML-2) Protease (Pro) has received little attention so far, although it is expressed in some disease contexts and other retroviral proteases are known to process cellular proteins. Results We set out to identify human cellular proteins that are substrates of HERV-K(HML-2) Pro employing a modified Terminal Amine Isotopic Labeling of Substrates (TAILS) procedure. Thousands of human proteins were identified by this assay as significantly processed by HERV-K(HML-2) Pro at both acidic and neutral pH. We confirmed cleavage of a majority of selected human proteins in vitro and in co-expression experiments in vivo. Sizes of processing products observed for some of the tested proteins coincided with product sizes predicted by TAILS. Processed proteins locate to various cellular compartments and participate in diverse, often disease-relevant cellular processes. A limited number of HERV-K(HML-2) reference and non-reference loci appears capable of encoding active Pro. Conclusions Our findings from an approach combining TAILS with experimental verification of candidate proteins in vitro and in cultured cells suggest that hundreds of cellular proteins are potential substrates of HERV-K(HML-2) Pro. It is therefore conceivable that even low-level expression of HERV-K(HML-2) Pro affects levels of a diverse array of proteins and thus has a functional impact on cell biology and possible relevance for human diseases. Further studies are indicated to elucidate effects of HERV-K(HML-2) Pro expression regarding human substrate proteins, cell biology, and disease. The latter also calls for studies on expression of specific HERV-K(HML-2) loci capable of encoding active Pro. Endogenous retrovirus-encoded Pro activity may also be relevant for disease development in species other than human. |
topic |
HERV-K Endogenous retrovirus Retroviral protease Proteolysis Pathogenesis Retrotransposon |
url |
http://link.springer.com/article/10.1186/s13100-019-0178-z |
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