An interaction domain in human SAMD9 is essential for myxoma virus host-range determinant M062 antagonism of host anti-viral function

Nounamo, Bernice; Li, Yibo; O'Byrne, Philomena; Kearney, Aoife M.; Khan, Amir R.; Liu, Jia

doi:10.1016/j.virol.2017.01.004

Cited by 28 publications

(37 citation statements)

References 30 publications

(54 reference statements)

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“…SAMD9 and SAMD9L-Very recently, sterile alpha motif domain-containing protein 9 (SAMD9) was shown to be a host innate antiviral factor against poxvirus (e.g. vaccinia and myxoma virus), Japanese encephalitis virus and low-risk Papillomavirus in humans (154)(155)(156)(157)(158)(159). Mutations in SAMD9 and its paralog SAMD9-like (SAMD9L) are associated with a heterogeneous clinical phenotype.…”

Section: Mda5-rare Heterozygous Gof Mutations Of Ifn-induced Helicasementioning

confidence: 99%

Lessons learned from the study of human inborn errors of innate immunity

Bucciol

Moens

Bosch

et al. 2019

Journal of Allergy and Clinical Immunology

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Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors.

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Section: Mda5-rare Heterozygous Gof Mutations Of Ifn-induced Helicasementioning

confidence: 99%

Lessons learned from the study of human inborn errors of innate immunity

Bucciol

Moens

Bosch

et al. 2019

Journal of Allergy and Clinical Immunology

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“…Liu and coworkers (22) described the formation of SAMD9containing granules, which appear related but not identical to typical stress granules, in the absence of C7/K1 of VACV or MO62 of myxoma virus. A mutagenesis study indicated that the N-terminal 385 amino acids of SAMD9 retain the ability to interact with MO62 but are insufficient to prevent replication of the host range mutants (26). SAMD9L, a paralog of SAMD9, also inhibits the C7/K1 mutant (27).…”

mentioning

confidence: 99%

Human Host Range Restriction of the Vaccinia Virus C7/K1 Double Deletion Mutant Is Mediated by an Atypical Mode of Translation Inhibition

Sivan

Glushakow-Smith

Katsafanas

et al. 2018

J Virol

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Replication of vaccinia virus in human cells depends on the viral C7 or K1 protein. A previous human genome-wide short interfering RNA (siRNA) screen with a C7/K1 double deletion mutant revealed SAMD9 as a principal host range restriction factor along with additional candidates, including WDR6 and FTSJ1. To compare their abilities to restrict replication, the cellular genes were individually inactivated by CRISPR/Cas9 mutagenesis. The C7/K1 deletion mutant exhibited enhanced replication in each knockout (KO) cell line but reached wild-type levels only in SAMD9 KO cells. SAMD9 was not depleted in either WDR6 or FTSJ1 KO cells, suggesting less efficient alternative rescue mechanisms. Using the SAMD9 KO cells as controls, we verified a specific block in host and viral intermediate and late protein synthesis in HeLa cells and demonstrated that the inhibition could be triggered by events preceding viral DNA replication. Inhibition of cap-dependent and -independent protein synthesis occurred primarily at the translational level, as supported by DNA and mRNA transfection experiments. Concurrent with collapse of polyribosomes, viral mRNA was predominantly in 80S and lighter ribonucleoprotein fractions. We confirmed the accumulation of cytoplasmic granules in HeLa cells infected with the C7/K1 deletion mutant and further showed that viral mRNA was sequestered with SAMD9. RNA granules were still detected in G3BP KO U2OS cells, which remained nonpermissive for the C7/K1 deletion mutant. Inhibition of cap-dependent and internal ribosome entry site-mediated translation, sequestration of viral mRNA, and failure of PKR, RNase L, or G3BP KO cells to restore protein synthesis support an unusual mechanism of host restriction. A dynamic relationship exists between viruses and their hosts in which each ostensibly attempts to exploit the other's vulnerabilities. A window is opened into the established condition, which evolved over millennia, if loss-of-function mutations occur in either the virus or host. Thus, the inability of viral host range mutants to replicate in specific cells can be overcome by identifying and inactivating the opposing cellular gene. Here, we investigated a C7/K1 host range mutant of vaccinia virus in which the cellular gene SAMD9 serves as the principal host restriction factor. Host restriction was triggered early in infection and manifested as a block in translation of viral mRNAs. Features of the block include inhibition of cap-dependent and internal ribosome entry site-mediated translation, sequestration of viral RNA, and inability to overcome the inhibition by inactivation of protein kinase R, ribonuclease L, or G3 binding proteins, suggesting a novel mechanism of host restriction.

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“…The identification of CP77 as yet another SAMD9L inhibitor underscores the critical role of SAMD9&L in host defense against poxviruses and the elaborate lengths OPXVs went to evade SAMD9&L. K1 and C7 were previously shown to function equivalently at inhibiting human and mouse SAMD9&L (25). In this study, however, we uncovered differences between K1/C7/CP77 in their targeting mechanism and binding specificity for SAMD9&L. While a C7 ortholog was shown to target the N-terminus of SAMD9 (39), both K1 and CP77 target an internal region containing the predicated NTPase and TPR domains. While any one of K1/C7/CP77 can bind mouse SAMD9L, only K1 can bind chSAMD9, and only CP77 can bind chSAMD9L.…”

Section: Discussionmentioning

confidence: 87%

“…5A). The N-terminal 385 aa of human SAMD9 (hSAMD9), which contains the predicted SAM and AlbA domains, was reported to be sufficient for binding to a poxvirus C7 homolog (39). To find out which region of hSAMD9 is targeted by K1, we constructed hSAMD9 mutants with deletions in different domains and tested the binding of the mutants to K1.…”

Section: Resultsmentioning

confidence: 99%

Identification of CP77 as the third orthopoxvirus SAMD9L inhibitor with a unique specificity for a rodent SAMD9L

Zhang

Meng

Townsend³

et al. 2019

Preprint

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24 25 Orthopoxviruses (OPXVs) have a broad host range in mammalian cells, but 26 Chinese hamster ovary (CHO) cells are non-permissive for vaccinia virus (VACV). Here, 27 IMPORTANCE: 47 Several OPXV species, including monkeypox virus and cowpox virus, cause 48 zoonotic infection in humans. They are believed to use wild rodents as the reservoir or 49 intermediate hosts, but the host or viral factors that are important for OPXV host range in 50 rodents are unknown. Here, we showed that the abortive replication of several OPXV 51 species in a Chinese hamster cell line was caused by a species-specific difference in the 52 host antiviral factor SAMD9L, indicating that SAMD9L divergence in different rodent 53 species poses a barrier for cross-species OPXV infection. While the Chinese hamster 54 SAMD9L could not be inhibited by two previously identified OPXV inhibitors of human 55 and mouse SAMD9L, it can be inhibited by cowpox virus CP77, indicating that OPXVs 56 encode three SAMD9L inhibitors with different specificity. Our data suggest that OPXV 57 host range in broad rodent species depends on three SAMD9L inhibitors with different 58 specificities. 59 60 (VPXV) are recognized as the North American OPXVs for being endemic in North 70America (2). VARV has been eradicated from nature, but the cessation of smallpox 71 vaccination and the waning of anti-OPXV herd immunity have increased the risk of 72 zoonotic OPXV infections. MPXV is highly virulent in humans (3), and the recent 73 increase in human monkeypox cases across a wide geographic area is a concern for 74 global health security (4). CPXV and VACV are responsible for zoonoses in Europe, 75Asia and South America (5, 6). Novel OPXV species have also been discovered in recent 76 human cases (7, 8), including Akhmeta virus (AKMV) isolated from the town of 77 Akhmeta, Georgia (country). 78OPXVs vary greatly in their animal host range (2), with some, such as VARV, 79 CMLV and TATV, only known to infect a single mammalian species, while others, such 80 as MPXV, CPXV and VACV, capable of infecting a wide variety of mammalian hosts. 81

show abstract

An interaction domain in human SAMD9 is essential for myxoma virus host-range determinant M062 antagonism of host anti-viral function

Cited by 28 publications

References 30 publications

Lessons learned from the study of human inborn errors of innate immunity

Lessons learned from the study of human inborn errors of innate immunity

Human Host Range Restriction of the Vaccinia Virus C7/K1 Double Deletion Mutant Is Mediated by an Atypical Mode of Translation Inhibition

Identification of CP77 as the third orthopoxvirus SAMD9L inhibitor with a unique specificity for a rodent SAMD9L

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