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

Abstract

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.

DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes

“…The latter were then correctly assigned to a different orthologous group than HERC5 . As previously reported in mammals ( 74 ), we identified strong evidence of positive selection on primate HERC6 (with five methods, Figure 2 ). This could mean that while both HERC5 and HERC6 have been evolving under positive selection in mammals, they have been subjected to different evolutionary constraints in primates, with a lower selective pressure on primate HERC5 vs HERC6 .…”

DGINN, an automated and highly-flexible pipeline for the Detection of Genetic INNovations on protein-coding genes

“…The latter were then correctly assigned to a different orthologous group than HERC5. As previously reported (Paparisto et al, 2018), we identified strong evidence of positive selection on HERC6 (with five methods, Figure 2). This could mean that while both HERC5 and HERC6 have been evolving under positive selection in mammals, they have been subjected to different evolutionary constraints in primates, with a lower selective pressure on primate HERC5 vs HERC6.…”

Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach

“…Low sample numbers precluded extensive validation in TCGA patient cohort; nevertheless a distinct alteration pattern of candidate genes was observed between HPV+ and HPV-cohorts of oropharyngeal cancers. A distinct set of prognosticators were identified for HPV+ and HPV-oropharyngeal cancers; ECHDC2, GGT6, HERC5 were showed to be associated with HPV+; HERC5 has a known anti-viral activity [78] [79] and its possible role in HNSCC HPV associated cancer is yet to be studied. On the other hand alterations in GRB10, EMILIN1, FNDC1, FOXF2 and HLX, determined poor prognosis in the HPV-cohort; this subset is involved in multiple carcinogenic processes in different solid tumors [80] [85].…”