Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Zhang, Fu‐Shun; Meng, Xiangzhi; Townsend, Michael; Satheshkumar, Panayampalli S.; Xiang, Yan

doi:10.1128/jvi.00225-19

Cited by 14 publications

(14 citation statements)

References 54 publications

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“…Interestingly, this SAMD9/SAMD9L inhibition is mediated by different, unrelated poxvirus proteins such as CPXV CP77 or K1 in some poxviruses. CPXV CP77 was recently shown to bind and inhibit Chinese hamster SAMD9L, which was not inhibited by VACV C7 or K1 [43]. In combination with the data we present in this study, these results emphasize the fact that immunomodulation is an important component of species-specificity.…”

Section: Discussionsupporting

confidence: 85%

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

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The antiviral protein kinase R (PKR) is an important restriction factor, which poxviruses must overcome to productively infect host cells. Many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus, to inhibit PKR. Although the interaction between PKR and eIF2a is highly conserved, some K3 orthologs were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that the amino acid combinations needed to mediate improved or diminished inhibition of PKR varied between different species. The data presented here show that even closely related species can display drastically different sensitivities to orthopoxvirus PKR inhibitors, and that orthologs from closely related poxviruses can show strong differences in their function. Furthermore, there is likely to be a limited number of possible mutations that disrupt K3-interactions but still maintain PKR/eIF2a interactions. Thus, by chance some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral host antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

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Section: Discussionsupporting

confidence: 85%

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

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“…SAMD9/9L are ubiquitously expressed in many tissues ( 15 ), and their expression can be further induced by interferons. Nearly all mammalian poxviruses encode at least one specific inhibitor against SAMD9/9L, with the prototypical poxvirus vaccinia encoding two inhibitors that target different regions of SAMD9/9L ( 16 , 17 ). The deletion of both SAMD9/9L inhibitors, K1 and C7, from vaccinia virus resulted in abortive replication in most mammalian cells due to a shut-off of global protein synthesis ( 18 – 20 ).…”

mentioning

confidence: 99%

Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L

Peng

Meng

Zhang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.

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“…Interestingly, SAMD9/SAMD9L inhibition can be mediated by different, unrelated poxvirus proteins such as CPXV CP77 or K1 in some poxviruses. CPXV CP77 was recently shown to bind and inhibit Chinese hamster SAMD9L, which was not inhibited by VACV C7 or K1 [ 44 ]. In combination with the data we present in this study, these results emphasize the fact that immunomodulation is an important component of viral species-specificity.…”

Section: Discussionmentioning

confidence: 99%

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

et al. 2021

View full text Add to dashboard Cite

The antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs from host-restricted poxviruses were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses, a genus with a generally broader host range. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, it is possible that by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

show abstract

Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Cited by 14 publications

References 54 publications

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

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