Evolution-Guided Structural and Functional Analyses of the HERC Family Reveal an Ancient Marine Origin and Determinants of Antiviral Activity.

Autor:	Paparisto E; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Woods MW; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Coleman MD; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Moghadasi SA; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Kochar DS; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Tom SK; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Kohio HP; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Gibson RM; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Rohringer TJ; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Hunt NR; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Di Gravio EJ; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Zhang JY; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Tian M; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Gao Y; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Arts EJ; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada., Barr SD; Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada stephen.barr@uwo.ca.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2018 Jun 13; Vol. 92 (13). Date of Electronic Publication: 2018 Jun 13 (Print Publication: 2018).
DOI:	10.1128/JVI.00528-18
Abstrakt:	In humans, homologous to the E6-AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing protein 5 (HERC5) is an interferon-induced protein that inhibits replication of evolutionarily diverse viruses, including human immunodeficiency virus type 1 (HIV-1). To better understand the origin, evolution, and function of HERC5, we performed phylogenetic, structural, and functional analyses of the entire human small-HERC family, which includes HERC3, HERC4, HERC5, and HERC6. We demonstrated that the HERC family emerged >595 million years ago and has undergone gene duplication and gene loss events throughout its evolution. The structural topology of the RCC1-like domain and HECT domains from all HERC paralogs is highly conserved among evolutionarily diverse vertebrates despite low sequence homology. Functional analyses showed that the human small HERCs exhibit different degrees of antiviral activity toward HIV-1 and that HERC5 provides the strongest inhibition. Notably, coelacanth HERC5 inhibited simian immunodeficiency virus (SIV), but not HIV-1, particle production, suggesting that the antiviral activity of HERC5 emerged over 413 million years ago and exhibits species- and virus-specific restriction. In addition, we showed that both HERC5 and HERC6 are evolving under strong positive selection, particularly blade 1 of the RCC1-like domain, which we showed is a key determinant of antiviral activity. These studies provide insight into the origin, evolution, and biological importance of the human restriction factor HERC5 and the other HERC family members. IMPORTANCE Intrinsic immunity plays an important role as the first line of defense against viruses. Studying the origins, evolution, and functions of proteins responsible for effecting this defense will provide key information about virus-host relationships that can be exploited for future drug development. We showed that HERC5 is one such antiviral protein that belongs to an evolutionarily conserved family of HERCs with an ancient marine origin. Not all vertebrates possess all HERC members, suggesting that different HERCs emerged at different times during evolution to provide the host with a survival advantage. Consistent with this, two of the more recently emerged HERC members, HERC5 and HERC6, displayed strong signatures of having been involved in an ancient evolutionary battle with viruses. Our findings provide new insights into the evolutionary origin and function of the HERC family in vertebrate evolution, identifying HERC5 and possibly HERC6 as important effectors of intrinsic immunity in vertebrates. (Copyright © 2018 Paparisto et al.)
Databáze:	MEDLINE
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