Biology subjects

Loyer, C.

Publications and source records attributed to Loyer, C..

3 recordsLinked to original sources

bioRxiv2025

Ancient convergence with prokaryote defense and recent adaptations to lentiviruses in primates characterize the ancestral immune factors SAMD9s

Human SAMD9 and SAMD9L are duplicated genes that encode innate immune proteins restricting poxviruses and lentiviruses, such as HIV, and implicated in life-threatening genetic diseases and cancer. Here, we combined structural similarity searches, phylogenetics and population genomics with experimental assays of SAMD9/9L functions to resolve the evolutionary and functional dynamics of these immune proteins, spanning from prokaryotes to primates. We discovered structural analogs of SAMD9/9L in the anti-bacteriophage defense system Avs, resulting from convergent evolution. Further, the predicted nuclease active site was conserved in bacterial analogs and was essential for cell death functions, suggesting a fundamental role in defense across different life kingdoms. Despite this ancestral immunity, we identified genomic signatures of evolutionary arms-races in mammals, with remarkable gene copy number variations targeted by natural selection. We further unveiled that the absence of SAMD9 in bonobos corresponds to a recent gene loss still segregating in the population. Finally, we found that chimp and bonobo SAMD9Ls have enhanced anti-HIV-1 functions, and that bonobo-specific SAMD9L polymorphisms confer increased anti-HIV-1 activity to human SAMD9L without compromising its effect on cell translation. These SAMD9/9L adaptations likely resulted from strong viral selective pressures, including by primate lentiviruses, and could contribute to lentiviral resistance in bonobos. Altogether, this study elucidates the interplay between ancient immune convergence across kingdoms and species-specific adaptations within the Avs9 and SAMD9/9L antiviral shared immunity. Significance statementThe SAMD9 gene family encodes antiviral factors of poxviruses and lentiviruses/HIV and is implicated in genetic diseases. Here, we found strong structural similarity with proteins from the Avs anti-bacteriophage system and uncovered ancient functional convergence in immune strategies between prokaryotes and metazoans. Within mammals, and more importantly in primates, we describe a highly dynamic evolutionary history of the SAMD9 gene family that underwent adaptive episodic gene losses. Unlike humans and chimps, some bonobos lack the SAMD9 gene entirely. Bonobos and chimps also possess unique variants of SAMD9L enhancing anti-HIV-1 activity without compromising cell functions, suggesting super-restrictors. This could also participate in shaping SIVcpz evolution and contribute to the absence of lentivirus-infected bonobos. Overall, the seeming dichotomy between the ancient evolutionary convergence in different kingdoms and recent functional adaptation within primates highlights the arms-races between key immune defense systems and viruses. This study paves the way for evolutionary medicine, where evolutionary-based discoveries may have application to human health, providing a deeper understanding of how the immune system adapts to fight viral infections over billion years of evolution.

evolutionary biology↗

bioRxiv2025

Genomic and functional adaptations in guanylate-binding protein 5 (GBP5) highlight specificities of bat antiviral innate immunity

Bats are asymptomatic reservoirs of several zoonotic viruses. This may result from long-term coevolution between viruses and bats, that have led to host adaptations contributing to an effective balance between strong antiviral responses with innate immune tolerance. To better understand these virus-host interactions, we combined comparative transcriptomics, phylogenomics and functional assays to characterize the evolution of bat innate immune antiviral factors. First, we stimulated the type I interferon immune pathway in Myotis yumanensis primary cells and identified guanylate-binding protein 5 (GBP5) as the most differentially expressed interferon-stimulated gene (ISG). Phylogenomic analyses showed that bat GBP5 has been under strong episodic positive selection, with numerous rapidly evolving sites and species-specific gene duplications, suggesting past evolutionary arms races. Functional tests on GBP5 orthologs from ten bat species covering the >60 million years of Chiroptera evolution revealed species- and virus-specific restrictions against RNA viruses (retrovirus HIV, and rhabdoviruses European bat lyssavirus and VSV), which are typical signatures of adaptations to past viral epidemics. Interestingly, we also observed a lineage-specific loss of the GBP5 prenylation motif in the common ancestor of Pipistrellus and Eptesicus bats, associated with different GBP5 subcellular localization and loss of antiviral functions. Resurrection of the ancestral prenylation motif in Eptesicus fuscus GBP5 rescued its subcellular localization, but not the complete antiviral activities, suggesting that additional determinants are necessary for the antiviral restriction. Altogether, our results highlight adaptations that contribute to bat specific immunity and provide insights into the functional evolution of antiviral effector GBP5. Key FindingsO_LIGBP5 is the most differentially expressed gene upon type I interferon stimulation of Myotis yumanensis primary cells. C_LIO_LIBat GBP5 has evolved under strong episodic genomic and genetic diversification, including early stop codon leading to protein truncation and loss of prenylation motif. C_LIO_LIGBP5 diversification in bats impacts their subcellular localization and antiviral functions. C_LIO_LIBat GBP5s exhibit species- and virus-specificity in their ability to inhibit infectivity of viral particles, bearing glycoproteins from retroviral HIV, vesicular stomatitis virus and European bat lyssavirus-1. C_LIO_LIResurrection of the ancestral prenylation motif in a bat GBP5 rescues its subcellular localization but not its full antiviral activity C_LI

immunology↗

bioRxiv2023

The inflammatory and tumor suppressor SAMD9L acts through a Schlafen-like box to restrict HIV and inhibit cell translation in SAAD/ATXPC

Sterile alpha motif domain-containing proteins 9 and 9L (SAMD9/9L) are associated with life-threatening genetic diseases and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated SAMD9L, and not SAMD9, restricts HIV-1 replication at the translation step, with a strong inhibition of Transmitted/Founder HIV-1 patient strains. More broadly, SAMD9L restricts primate lentiviruses, but not another retrovirus (MLV) or two ssRNA viruses (MOPV, VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a Schlafen(SLFN)-like active site necessary for HIV-1 restriction. By testing a germline gain-of-function variant from patients with SAMD9L-associated autoinflammatory disease (SAAD) and ataxia-pancytopenia (ATXPC), we determined that SAMD9L cellular and pathogenic functions also depend on the SLFN-like active site. Finally, we propose a model in which SAMD9L translational repression could be dependent on codon-usage, linking its cellular function and the virus-specific innate immunity. The identification of another Achilles heel of HIV, as well as the inflammatory SAMD9L effector and auto-regulatory determinants, provide novel avenues against infectious and genetic diseases. Significance statementThis study identifies SAMD9L as a potent HIV-1 antiviral factor from the interferon immunity and deciphers the host determinants underlying SAMD9L translational repression. The characterization of SAMD9L activity and determinants is also of medical importance for patients with rare genetic diseases bearing deleterious mutations in SAMD9L or with specific cancers. We demonstrate that a pathogenic SAMD9L patients variant is inactivated by the mutation of an identified active site in a SLFN-like box, resulting in an abolished translational shutdown. Furthermore, we describe SAMD9L, but not SAMD9, as an antiviral factor of HIV and lentiviruses, through a translational repression mediated by the SLFN-like box and potentially dependent on codon usage. These findings may have implications to better fight against HIV/AIDS as well as SAAD/ATXPC. Key findings- SAMD9L, but not SAMD9, restricts HIV-1, including Transmitted/Founder patient strains. - SAMD9L broadly restricts primate lentiviruses, but not the retrovirus MLV, nor two ssRNA viruses, the Rhabdovirus VSV and the Arenavirus MOPV. - SAMD9L inhibits viral and cellular translation through an essential E198/D243 active site in a SLFN-like box. - The SAMD9L-associated autoinflammatory disease (SAAD) F886Lfs*11 variant has enhanced HIV translational repression, unveiling an autoregulatory domain of the anti-lentiviral function.

immunology↗